Distant Intracranial Recurrence Research Articles

PATH-41. PRIMARY BRAIN SARCOMA WITH DROP METASTASES AND LEPTOMENINGEAL DISEASE

Abstract INTRODUCTION Primary brain sarcoma is extremely rare and has a very poor prognosis. Sarcomas are a highly diverse group, with over 100 different subtypes identified in the recent WHO classification. Case: In this case, we describe a 51-year-old man diagnosed with primary right frontal poorly differentiated sarcoma. He experienced cognitive changes for weeks. Brain MRI revealed a lobulated mass with peripheral enhancement measuring 67 mm by 61 mm by 52 mm. He underwent gross total resection, and pathology indicated high-grade poorly differentiated sarcomatous lesions. Further analysis at Memorial Sloan Kettering and NIH failed to match any DNA methylation class. Next generation sequence (NGS) testing revealed mutation of NF2, CDKN2A, COL3A1, CD33, and PIK3CA genes, increased PD-L1 mRNA, and PD-L1 expression, greater than 50%. The conclusive diagnosis was a PD-L1 high poorly differentiated sarcoma, not otherwise specified. Since no primary site was found elsewhere, planned to treat it as a primary brain sarcoma. Patient underwent focal radiation therapy with a plan to start immunotherapy combination of anti-CTLA4 and anti-PD1 therapy. In addition, an anti-VEGF therapy with pazopanib because of the efficacy of pazopanib in the setting of soft tissue sarcomas. The patient completed IMRT on 07/13/2023 and presented with a new onset of left leg weakness and urinary incontinence on 07/25/2024, further neuraxis imaging with MRI showed local and distant intracranial recurrence with drop metastasis at C1, C5-C6, and S2. The patient was started on IMRT to address drop metastasis, however further clinical decline led to treatment discontinuation. DISCUSSION There is no consensus on treatment guidelines on primary brain sarcomas given that they are exceedingly rare. DNA methylation and NGS provided very valuable information. We were unable to find any reported cases of primary brain sarcoma with drop metastases and leptomeningeal disease in the literature.

Long-Term Intracranial Outcomes With Combination Dual Immune-Checkpoint Blockade and Stereotactic Radiosurgery in Patients With Melanoma and Non-Small Cell Lung Cancer Brain Metastases

The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone. Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts. The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs.

RADT-15. INTRACRANIAL OUTCOMES OF DUAL IMMUNE-CHECKPOINT INHIBITION AND SRS COMBINATION IN PATIENTS WITH MELANOMA AND NSCLC BRAIN METASTASES

Abstract INTRODUCTION The intracranial benefit of offering dual immune checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to melanoma and non-small cell lung cancer (NSCLC) patients receiving SRS for brain metastases is unknown. We hypothesized that D-ICPI improves local control compared to SRS alone. METHODS Melanoma and NSCLC patients treated with SRS between 2016-2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS 288 patients (44% melanoma, 56% NSCLC) with 1,704 brain metastases were included. 53% of patients had symptomatic metastases. Median follow up was 58.8 months. Patients were treated with D-ICPI (28%), S-ICPI (45%), or SRS alone (27%). 12-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95%CI:91.11-96.90%), 91.72% (89.29-93.64%), and 88.22% (84.06-91.41%). Only D-ICPI was significantly associated with reduced LR (p = 0.0032). 173 patients (60%) developed IP. The 12-month cumulative incidence of IP was 41.27% (95%CI:30.27-51.92%), 51.86% (42.78-60.19%), and 57.15% (44.98-67.59%) following D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (p = 0.0408). On multivariate Cox regression, D-ICPI (HR:0.595,95%CI:0.373-0.951,p = 0.0300) and presentation with &amp;gt;10 BMs (2.492,1.68-3.725,p &amp;lt; .0001) remained significantly correlated with IP. Median OS following D-ICPI, S-ICPI, and SRS alone was 26.1 (95%CI:15.5-40.7), 21.5 (16.5-29.6) and 17.5 (11.3-23.8) months. Only D-ICPI trended toward improved OS (p = 0.0772). S-ICPI, fractionation, and timing of immunotherapy were not predictive of clinical outcomes. CONCLUSIONS The addition of D-ICPI for melanoma and NSCLC patients undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for symptomatic brain metastasis patients, regardless of fractionation or immunotherapy timing. Toxicity with this combination should be evaluated and balanced against clinical benefits.

Intracranial Control with Combined Dual Immune-Checkpoint Blockade and SRS for Melanoma and NSCLC Brain Metastases

It is unknown whether the use of dual immune-checkpoint inhibition (D-ICI) combined with stereotactic radiosurgery (SRS) affects local control of brain metastases (BMs). We sought to characterize the efficacy of SRS and D-ICI in patients with BMs in a large, single-institution cohort. Patients with melanoma and non-small cell lung cancer (NSCLC) BMs treated with SRS from January 1, 2016 to August 1, 2022 were evaluated. Patients were stratified by treatment with D-ICI versus single ICI (S-ICI). Concurrent ICI was defined as ICI given within four weeks of SRS. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. One thousand seven hundred four SRS-treated BMs from 288 patients met inclusion criteria. 55% of patients were symptomatic from their BMs at presentation. Median age, KPS, number of lesions, and SRS courses were 64 (Q1Q3:56-70.5), 90 (80-90), 2 (1-4), and 1 (1-2), respectively. One hundred twenty-eight (44%) melanoma and 160 (56%) NSCLC patients were included. 82 (28.5%), 129 (44.8%), and 77 (26.7%) patients were treated with D-ICI, S-ICI, or SRS alone. Median SRS dose, fractions, and PTV were 20 (Q1Q3:20-25), 1 (1-5), and 0.3cc3 (0.1-1.2). The median follow-up was 14.3 months. One hundred twenty-seven (7.45%) BMs recurred post-SRS and the median time to LR was 4.8 months (Q1Q3:3.0-9.2). On competing risk analysis, LR was significantly reduced with D-ICI (HR: 0.452, p = 0.0024), but not with S-ICI (HR: 0.693, p = 0.0596) compared to SRS alone. The 1-year LR was 3.77% (95% CI = 2.19-6.00), 6.8% (5.19-8.70), and 8.96% (6.48-11.93) with D-ICI, S-ICI, and SRS alone. The median time to IP was 4.1 months (Q1Q3 = 2.9-9.5). On competing risk analysis, IP was significantly reduced with D-ICI (HR = 0.638, p = 0.031), but not with S-ICI (HR = 0.756, p = 0.106) compared to SRS alone. 1-year IP was 40.05% (95% CI = 29.14-50.70), 51.86% (42.78-60.19), and 58.49% (46.30-68.84) with D-ICI, S-ICI, and SRS alone. Concurrent delivery of D-ICI and SRS significantly reduced IP (HR = 0.463, p = 0.0071), whereas other combinations of timing and ICI did not reach significance. Median OS was 11.9 months after SRS. On Kaplan Meier analysis, OS was significantly improved with D-ICI (HR = 0.616, 95% CI = 0.412-0.923, p = 0.019), but not with S-ICI (HR = 0.877, 95% CI = 0.633-1.217, p = 0.433) compared to SRS alone. Hospitalizations (p = 0.021) and immune-related adverse events (irAEs) (p<0.001) were increased with D-ICI. Any grade radiation necrosis (RN) was also increased with D-ICI (p = 0.013), but neurologic adverse events were comparable across cohorts (p = 0.572). D-ICI combined with SRS was associated with improved local control, intracranial control, and overall survival compared to SRS alone, whereas S-ICI was not associated with an improvement in these outcomes. However, D-ICI was also associated with increased risks of irAEs and RN.

CDKN2A/B co-deletion is associated with increased risk of local and distant intracranial recurrence after surgical resection of brain metastases.

While genetic alterations in brain metastases (BMs) have been previously explored, there are limited data examining their association with recurrence after surgical resection. This study aimed to identify genetic alterations within BMs associated with CNS recurrence after surgery across multiple cancer types. A retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical and gene sequencing data available. Local and remote CNS recurrence were the primary study outcomes. Next-generation sequencing of the coding regions in over 500 oncogenes was performed in brain metastasis specimens. Cox proportional hazards analyses were performed to identify clinical features and genomic alterations associated with CNS recurrence. A total of 90 patients undergoing resection of 91 BMs composed the cohort. Genes most frequently mutated in the cohort included TP53 (64%), CDKN2A (37%), TERT (29%), CDKN2B (23%), NF1 (14%), KRAS (14%), and PTEN (13%), all of which occurred across multiple cancer types. CDKN2A/B co-deletion was seen in 21 (23.1%) brain metastases across multiple cancer types. In multivariate Cox proportional hazard analyses including patient, tumor, and treatment factors, CDKN2A/B co-deletion in the brain metastasis was associated with increased risk of local (HR 4.07, 95% CI 1.32-12.54, P = 0.014) and remote (HR 2.28, 95% CI 1.11-4.69, P = 0.025) CNS progression. Median survival and length of follow-up were not different based on CDKN2A/B mutation status. CDKN2A/B co-deletion detected in BMs is associated with increased CNS recurrence after surgical resection. Additional work is needed to determine whether more aggressive treatment in patients with this mutation may improve outcomes.

Abstract PO-068: S100A9 mediates radiation resistance of brain metastasis

Abstract Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While whole-brain-radiation-therapy (WBRT) historically has been the gold standard in the management of brain metastasis patients, clinical practice rapidly adapted the frequent use of stereotactic radiosurgery (SRS), given the high incidence of neurotoxicity when giving WBRT. However, WBRT continuous to be an important treatment option, since many patients present with numerous multifocal lesions, high risk of SRS-associated radionecrosis, bad performance scores or probable distant intracranial recurrence, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. In spite of this clinical data, the underlying molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. As a proof of concept, we also detected S100A9 in serum and CSF samples from brain metastasis patients, complementing our biomarker strategy with a less invasive approach. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient. Citation Format: Lauritz Miarka, Catia Monteiro, Celine Dalmasso, Natalia Yebra, Coral Fustero-Torre, Aisling Hegarty, Stephen Keelan, Eduardo Caleiras, Vareslija Damir, Leonie Young, Riccardo Soffietti, Juan M. Sepúlveda, Angel Pérez, Aurelio Lain, Aurore Siegfied, Elizabeth Cohen-Jonathan Moyal, Manuel Valiente. S100A9 mediates radiation resistance of brain metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-068.

Sector Irradiation vs. Whole Brain Irradiation After Resection of Singular Brain Metastasis-A Prospective Randomized Monocentric Trial.

To minimize recurrence following resection of a cerebral metastasis, whole-brain irradiation therapy (WBRT) has been established as the adjuvant standard of care. With prolonged overall survival in cancer patients, deleterious effects of WBRT gain relevance. Sector irradiation (SR) aims to spare uninvolved brain tissue by applying the irradiation to the resection cavity and the tumor bed. 40 were randomized to receive either WBRT (n = 18) or SR (n = 22) following resection of a singular brain metastasis. Local tumor control was satisfactory in both groups. Recurrence was observed earlier in the SR (median 3 months, 1–6) than in the WBRT cohort (median 8 months, 7–9) (HR, 0.63; 95% CI, 0.03–10.62). Seventeen patients experienced a distant intracranial recurrence. Most relapses (n = 15) occurred in the SR cohort, whereas only two patients in the WBRT group had new distant tumor manifestation (HR, 6.59; 95% CI, 1.71–11.49; p = 0.002). Median overall survival (OS) was 15.5 months (range: 1–61) with longer OS in the SR group (16 months, 1–61) than in the WBRT group (13 months, 3–52), without statistical significance (HR, 0.55; 95% CI, 0.69–3.64). Concerning neurocognition, patients in the SR group improved in the follow-up assessments, while this was not observed in the WBRT group. There were positive signals in terms of QOL within the SR group, but no significant differences in the global QLQ and QLQ-C30 summary scores were found. Our results indicate comparable efficacy of SR in terms of local control, with better maintenance of neurocognitive function. Unsurprisingly, more distant intracranial relapses occurred. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01667640.

Impact of Systemic Therapy Type and Timing on Intracranial Tumor Control in Patients with Brain Metastasis from Non-Small-Cell Lung Cancer Treated With Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) can effectively control brain metastasis (BRM) from non-small-cell lung cancer (NSCLC), although intracranial recurrence from untreated micrometastatic tumor deposits is common without whole-brain radiotherapy. Our goal was to determine if immunotherapy improves distant intracranial progression-free survival (DI-PFS) compared with other systemic therapies in patients treated with SRS. All patients from 2011 to 2019 treated with SRS without previous whole-brain radiotherapy for NSCLC BRM were reviewed. DI-PFS for the entire cohort, and subgroups of patients, was estimated and compared using the Kaplan-Meier/log-rank method. One hundred and thirty-six SRS sessions used to treat 99 patients were reviewed; 98 (72%) for previously untreated BRM and 38 (28%) for recurrent BRM. 35% received immunotherapy (77% concurrent with SRS), 46% received chemotherapy (75% concurrent), and 18% received epidermal growth factor receptor/anaplastic lymphoma kinase (ALK) targeted therapy (85% concurrent). At median follow-up of 13.7 months, 49% developed distant intracranial recurrence. One-year DI-PFS was improved with any use of immunotherapy (58% vs. 39%; P= 0.03) and concurrent immunotherapy versus chemotherapy or targeted therapy (67% vs. 37% vs. 39%, respectively; P= 0.01). In the immunotherapy cohort, 1-year DI-PFS was improved for programmed death-ligand 1 expression ≥50% versus 1%-49% versus 0% (80% vs. 49% vs. 19%, respectively; P < 0.01), and Lung Immune Prognostic Index 0-1 versus 2 (63% vs. 34%; P= 0.03). Immunotherapy concurrent with SRS, particularly in patients with high programmed death-ligand 1 expression or low Lung Immune Prognostic Index, is associated with improved DI-PFS and no increased risk of radiation necrosis compared with other systemic therapies for NSCLC.

The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI).

Recent advances in targeted therapy have prolonged overall survival (OS) for patients with lung cancer. The impact of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) on brain metastases (BM) treated with stereotactic radiosurgery (SRS) has not, however, been fully elucidated. We investigated the influence of post-SRS EGFR-TKI use on the efficacy and toxicity of SRS for BM from lung adenocarcinoma. We used the updated dataset of the Japanese Leksell Gamma Knife (JLGK) 0901 study, which proved the efficacy of Gamma Knife SRS in patients with BM. Propensity score matching (PSM) analysis was employed to determine the impact of concurrent or post-SRS EGFR-TKI use on OS, neurological death, intracranial disease recurrence and SRS-related adverse events. Among 1194 patients registered in the JLGK0901 study, 608 eligible lung adenocarcinoma patients were identified and 238 (39%) had received EGFR-TKI concurrently or during the post-SRS clinical course. After PSM, there were 200 patient pairs with/without post-SRS EGFR-TKI use. EGFR-TKI use was associated with longer OS (median 25.5 vs. 11.0months, HR 0.60, 95% CI 0.48-0.75, p < 0.001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45, 95% CI 1.12-1.89, p = 0.005). Neurological death, local recurrence and SRS-related adverse event rates did not differ significantly between the two groups. Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use.

Radiological Kinetics of Brain Metastases and Clinical Implications for Patients Treated With Stereotactic Radiosurgery

AimsSelect patients with brain metastases receive stereotactic radiosurgery (SRS) with the objective of improving survival and intracranial disease control. Brain metastases number and volume are prognostic factors used to inform patient selection. The aim of this study was to assess the rate of change of brain metastases size and number (growth kinetics) between the diagnostic and day of SRS magnetic resonance imaging (MRI) scans. Materials and MethodsAll patients treated with Gamma Knife SRS between October 2015 and April 2017 were included in this single-centre retrospective analysis. Brain metastases number and diameter were recorded at diagnosis and treatment. For patients with multiple brain metastases, the largest lesion was the index lesion. Distant intracranial control and overall survival were reported from the date of SRS. ResultsIn total, 146 patients received 156 episodes of SRS. The median interval between diagnostic and SRS MRI was 20 days (range 1–68). Interval growth in the index lesion of at least 3 mm or the development of a new brain metastasis was noted in 60.2% of patients. This was associated with age less than 60 years (P = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status 2 or above (P = 0.04), non-small cell lung carcinoma (NSCLC) (P = 0.03) or melanoma histologies (P = 0.05) and uncontrolled extracranial disease (P = 0.05). These patients were also more likely to develop distant intracranial recurrence (P = 0.046). Clinically significant growth was not associated with scan interval or differences in overall survival. The Kaplan–Meier estimate of probability of survival at 12 months was 59.3% (95% confidence interval 46.7–75.2%) for all patients. ConclusionIntracranial progression between diagnosis and day of SRS is common. Risk factors are uncontrolled extracranial disease, poorer performance status, NSCLC or melanoma histologies and age less than 60 years. These patients would benefit from an MRI closer to treatment to inform patient selection and target delineation for SRS planning.

Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients

ObjectivesRecent advances in target therapies have prolonged overall survival (OS) for patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. The impact of EGFR mutations on stereotactic radiosurgery (SRS) for brain metastases (BM) has yet to be determined. The present study sought to evaluate the efficacy and limitations of SRS, administered with EGFR-tyrosine kinase inhibitors (TKI), for BM from EGFR-mutant lung adenocarcinoma. Materials and methodsThis retrospective observational study analyzed data from patients with BM arising from EGFR-mutant lung adenocarcinoma who received upfront Gamma Knife SRS between December 2010 and April 2016. OS and distant and local intracranial disease control rates were calculated. The prognostic factors for each event were also determined. ResultsOne hundred thirty-three consecutive patients (47 males/86 females) were eligible. The median age was 69 years, and the median Karnofsky performance status (KPS) was 90. Sixty-six patients (50%) had no history of EGFR-TKI use at the time of SRS. EGFR-TKI were administered to 85% of EGFR-TKI naïve patients after SRS. One- and 2-year OS rates were 74% and 52%, respectively. One- and 2-year distant BM recurrence rates (per patient) after SRS were 34% and 53%, respectively. One- and 2-year rates of local tumor control (per lesion) were 97% and 95%, respectively. Multivariate proportional hazards analyses showed that being EGFR-TKI naïve was associated with longer OS (HR: 0.42, P < 0.001), a lower distant intracranial recurrence rate (HR: 0.61, P = 0.037) and a higher local tumor control rate (HR: 0.28, P = 0.001). ConclusionsThe present study demonstrated the upfront SRS strategy to offer a minimally invasive and effective treatment option for EGFR-mutant lung adenocarcinoma patients with limited BM. EGFR-TKI naïve patients were found to be a distinct subgroup for which a longer survival time and durable intracranial disease control can be expected.

Three or More Courses of Stereotactic Radiosurgery for Patients with Multiply Recurrent Brain Metastases.

Although patients with brain metastasis are treated with primary stereotactic radiosurgery (SRS), the use of salvage therapies and their consequence remains understudied. To study the intracranial recurrence patterns and salvage therapies for patients who underwent multiple SRS courses. A retrospective review was performed of 59 patients with brain metastases who underwent ≥3 SRS courses for new lesions. Cox regression analyzed factors predictive for overall survival. The median age at diagnosis was 52 years. Over time, patients underwent a median of 3 courses of SRS (range: 3-8) to a total of 765 different brain metastases. The 6-month risk of distant intracranial recurrence after the first SRS treatment was 64% (95% confidence interval: 52%-77%). Overall survival was 40% (95% confidence interval: 28%-53%) at 24 months. Only 24 patients (41%) had a decline in their Karnofsky Performance Status ≤70 at last office visit. Quality of life was preserved among 77% of patients at 12months, with 45% experiencing clinically significant improvement during clinical follow-up. Radiation necrosis developed in 10 patients (17%). On multivariate analysis, gender (males, Hazard Ratio [HR]: 2.0, P < .05), Karnofsky Performance Status ≤80 (HR 3.2, P < .001), extracranial metastases (HR: 3.6, P < .001), and a distant intracranial recurrence ≤3 months from initial to repeat SRS (HR: 3.8, P < .001) were associated with a poorer survival. In selected patients, performing ≥3 SRS courses controls intracranial disease. Patients may need salvage SRS for distant intracranial relapse, but focal retreatments are associated with modest toxicity, do not appear to negatively affect a patient's performance status, and help preserve quality of life.

Radiation therapy in the management of breast cancer brain metastases: the impact of receptor status on treatment response, intracranial recurrence, and survival

Breast cancer is the second most common cancer to metastasize in the brain. Little is known about how receptor subtype, including luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched, and triple negative (TN) affect response to radiation and distant intracranial recurrence (ICR) following radiation therapy. We conducted a single-institution retrospective analysis of 38 breast cancer brain metastasis (BCBM) patients who underwent 93 treatment courses of stereotactic radiosurgery, stereotactic radiotherapy, post-operative radiation, or whole brain radiation therapy. Endpoints included overall survival (OS), treatment response (partial/complete response, PR/CR, or progression), ICR after treatment, and time from breast cancer diagnosis to the first BCBM (time to metastasis, TTM). Subset analyses were performed for triple receptor subtype as well as estrogen receptor (ER) positive versus negative, HER2+ versus HER2-, and age ≤ 50 versus >50 years old. Median OS for the population was 22.5 months, with median follow-up after treatment of 20.5 months. TTM was shortest for HER2 enriched, TN, ER−, and younger patients. TN, HER2-, and younger patients showed the poorest OS. ICR was also greatest in TN and HER2− patients. Radiation failure at the treated BCBM was seen most prominently in HER2+ and ER− patients. Receptor subtypes that demonstrated poorer OS tended to demonstrate higher intracranial recurrence. A positive response to radiation was not associated with better OS or lower ICR. Identifying patterns based on receptor subtype may guide clinicians in management and surveillance for BCBM.

Unyielding progress: recent advances in the treatment of central nervous system neoplasms with radiosurgery and radiation therapy.

In the past decade, our understanding of the roles of external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS) in the management of brain tumors has dramatically improved. To highlight the changes and contemporary treatment approaches, we review the indications and outcomes of ionizing radiation for benign intracranial tumors and brain metastases. For nonfunctioning pituitary adenomas, SRS is able to achieve radiographic tumor control in at least 90 % of cases. The rate of SRS-induced endocrine remission for functioning pituitary adenomas depends on the tumor subtype, but it is generally lower than the rate of radiographic tumor control. The most common complications from pituitary adenoma SRS treatment are hypopituitarism and cranial neuropathies. SRS has become the preferred treatment modality for vestibular schwannomas and skull base meningiomas less than 3 cm in size. Large vestibular schwannomas and meningiomas remain best managed with initial surgical resection or EBRT for surgically ineligible patients. For small to moderately sized brain metastases, there has been a shift toward treatment of newly diagnosed patients with SRS alone due to similar local control rates compared with surgical resection. RCTs have shown combined SRS and whole brain radiation therapy (WBRT) for brain metastases to decrease rates of local and distant intracranial recurrence compared to SRS alone. However, the improved intracranial control comes at the expense of poorer neurocognitive outcomes and without prolonging overall survival. Therefore, WBRT is generally reserved for salvage therapy. While EBRT has been frequently supplanted by SRS for the treatment pituitary adenomas and brain metastases, it still proves useful in selected cases of large lesions which are not amenable to surgical debulking or for those with widespread disease, poor performance status, and short life expectancy. In recent years, the scope of SRS has extended beyond the intracranial space to include extradural and intradural spinal tumors.

Influence of BRAF and NRAS Mutations on Distant Intracranial Recurrence and Survival in Metastatic Melanoma Following Radiosurgery

The clinical course of patients with metastatic melanoma with brain metastases can be quite varied. This study aims to compare outcomes based on mutational status of BRAF and NRAS following stereotactic radiosurgery (SRS). A prospectively maintained database of patients receiving SRS between November 2002 and December 2012 was queried to determine the rate of new brain metastasis development in patients with metastatic melanoma following SRS. Patients receiving whole brain radiation therapy as first line treatment were excluded. BRAF and NRAS mutational status was determined by Sanger sequencing. The impact of mutation status on risk of distant intracranial recurrence and overall survival (OS) from brain metastasis diagnosis was determined using Poisson regression with robust estimation of errors and Cox proportional hazards analyses, respectively. Other factors including systemic disease control and intracranial disease burden were explored as potential predictors of recurrence and OS in a similar fashion. One hundred eight patients were identified with a mean age of 63 years (range, 24-90 years), of which 68% were male and 94.4% were white. A NRAS mutation was found in 9 patients (8.3%) and BRAF mutation in 24 (22.2%). Median OS from brain metastasis diagnosis was 312 days (range, 228-471 days). A larger number of brain metastases at diagnosis and uncontrolled systemic disease were found to be univariate predictors of worsened OS (HR 1.04, p = 0.012; HR 2.52, p = 0.001, resp). Only uncontrolled systemic disease was a significant predictor of OS on multivariate analysis (HR 10.63, p = 0.022). Mutation status for BRAF and NRAS did not appear to influence survival in our cohort. NRAS-mutated patients were found to be at significantly higher risk of distant intracranial recurrence as compared to wild type patients (IRR for wild type compared to NRAS-mutated, 0.27, p = 0.011). No other variables were found to be significant predictors of recurrence. Although metastatic melanoma follows a highly variable clinical course, NRAS mutations appear to influence the number of intracranial recurrences experienced by patients. Other disease factors including systemic disease control and number of brain metastases at diagnosis seem to influence OS.

Fifty percent patients avoid whole brain radiotherapy: stereotactic radiotherapy for multiple brain metastases. A retrospective analysis of a single center

To summarize the outcomes of stereotactic radiotherapy (SRT), with or without whole-brain radiotherapy (WBRT), in the treatment of multiple brain metastasis and to explore the status of WBRT and SRT in the management of multiple brain metastasis. From May 1995 to April 2010, 98 patients with newly diagnosed, multiple brain metastasis were treated in our center. Forty-four patients were treated with SRT alone for the initial treatment, and 54 were treated with SRT+WBRT. Kaplan-Meier and Cox proportional hazards regression analyses were used for the survival analysis. The median survival time (MST) was 13.5months. No difference was observed in MST between the SRT and the SRT+WBRT groups (p=0.578). The Karnofsky Performance Score at the time of treatment (p=0.025), the interval time between diagnosis of primary tumor and brain metastasis (P=0.012) and the situation of extracranial disease (p=0.018) were significant predictors of survival. The crude distant intracranial recurrence (DIR) rates were 47.7% in the SRT group and 24.1% in the SRT+WBRT group (p=0.018). In addition, 52.3% patients in the SRT group were free from DIR and did not require WBRT in their whole lives. Our data suggest that use of SRT as the initial treatment while reserving WBRT as the salvage therapy in case of distant intracranial recurrence made about 50% of the patients avoid WBRT throughout the course of their lives and may be another optional treatment modality for multiple brain metastases.