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Outcomes of Gamma Knife Radiosurgery for Brain Metastases in the Motor Cortex

Prasad, Shefalika; Alzate, Juan Diego; Mullen, Reed; Bernstein, Kenneth; Qu, Tanxia; Silverman, Joshua; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:To study the clinical, imaging, and survival outcomes in patients with motor cortex brain metastases treated with stereotactic radiosurgery (SRS). METHODS:Imaging and clinical data were obtained from our prospective patient registry. Tumor volumes were obtained from serial imaging data. RESULTS:The outcomes of 208 patients with metastases involving the motor cortex who underwent SRS between 2012 and 2021 were analyzed. A total of 279 metastases (0.01 cm3-12.18 cm3, mean 0.74 cm3) were irradiated. The SRS margin dose varied from 10 to 20 Gy (mean 16.9 Gy). The overall tumor control rate was 97.8%. Perilesional edema was noted in 69 (25%) tumors at presentation. Adverse radiation effects (ARE) were noted in 6% of all tumors but were symptomatic in only 1.4%. Median time to appearance of symptomatic ARE was 8 months. Edema without ARE was observed in 13%. New focal seizures were noted in 5 patients (2%) and new generalized seizures in 1 patient (0.3%). Thirty-six patients (17%) presented with motor deficits. At final follow-up, 32 (85%) were improved or unchanged, 13 (41%) had a normal examination, 10 (31%) had mild deficits, and 9 (28%) still had moderate deficits. New remote brain metastases were found in 31% of patients at a median of 8 months. After treatment, the Karnofsky performance score distribution of the population showed an overall right shift and a median survival of 10 months. Patients with incidentally found brain metastases had significantly better survival than those presenting with deficits (median 13 vs 9 months) (P = .048). Absence of a neurological deficit, recursive partitioning analysis Class I and II, and dose >18 Gy were each associated with a significant survival advantage. CONCLUSION/CONCLUSIONS:SRS for motor cortex metastases is safe in most patients and effective in providing tumor control. Patients treated before neurological deficits develop show better outcomes.
PMID: 37823677
ISSN: 1524-4040
CID: 5571202

Long-term Survival From Breast Cancer Brain Metastases in the Era of Modern Systemic Therapies

Mashiach, Elad; Alzate, Juan Diego; De Nigris Vasconcellos, Fernando; Bernstein, Kenneth; Donahue, Bernadine R; Schnurman, Zane; Gurewitz, Jason; Rotman, Lauren E; Adams, Sylvia; Meyers, Marleen; Oratz, Ruth; Novik, Yelena; Kwa, Maryann J; Silverman, Joshua S; Sulman, Erik P; Golfinos, John G; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:Median survival for all patients with breast cancer with brain metastases (BCBMs) has increased in the era of targeted therapy (TT) and with improved local control of intracranial tumors using stereotactic radiosurgery (SRS) and surgical resection. However, detailed characterization of the patients with long-term survival in the past 5 years remains sparse. The aim of this article is to characterize patients with BCBM who achieved long-term survival and identify factors associated with the uniquely better outcomes and to find predictors of mortality for patients with BCBM. METHODS:We reviewed 190 patients with breast cancer with 931 brain tumors receiving SRS who were followed at our institution with prospective data collection between 2012 and 2022. We analyzed clinical, molecular, and imaging data to assess relationship to outcomes and tumor control. RESULTS:The median overall survival from initial SRS and from breast cancer diagnosis was 25 months (95% CI 19-31 months) and 130 months (95% CI 100-160 months), respectively. Sixteen patients (17%) achieved long-term survival (survival ≥5 years from SRS), 9 of whom are still alive. Predictors of long-term survival included HER2+ status (P = .041) and treatment with TT (P = .046). A limited number of patients (11%) died of central nervous system (CNS) causes. A predictor of CNS-related death was the development of leptomeningeal disease after SRS (P = .025), whereas predictors of non-CNS death included extracranial metastases at first SRS (P = .017), triple-negative breast cancer (P = .002), a Karnofsky Performance Status of <80 at first SRS (P = .002), and active systemic disease at last follow-up (P = .001). Only 13% of patients eventually needed whole brain radiotherapy. Among the long-term survivors, none died of CNS progression. CONCLUSION/CONCLUSIONS:Patients with BCBM can achieve long-term survival. The use of TT and HER2+ disease are associated with long-term survival. The primary cause of death was extracranial disease progression, and none of the patients living ≥5 years died of CNS-related disease.
PMID: 37581437
ISSN: 1524-4040
CID: 5564632

Extended Survival in Patients With Non-Small-Cell Lung Cancer-Associated Brain Metastases in the Modern Era

Berger, Assaf; Mullen, Reed; Bernstein, Kenneth; Alzate, Juan Diego; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Chachoua, Abraham; Shum, Elaine; Velcheti, Vamsidhar; Sabari, Joshua; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:Brain metastases (BM) have long been considered a terminal diagnosis with management mainly aimed at palliation and little hope for extended survival. Use of brain stereotactic radiosurgery (SRS) and/or resection, in addition to novel systemic therapies, has enabled improvements in overall and progression-free (PFS) survival. OBJECTIVE:To explore the possibility of extended survival in patients with non-small-cell lung cancer (NSCLC) BM in the current era. METHODS:During the years 2008 to 2020, 606 patients with NSCLC underwent their first Gamma Knife SRS for BM at our institution with point-of-care data collection. We reviewed clinical, molecular, imaging, and treatment parameters to explore the relationship of such factors with survival. RESULTS:The median overall survival was 17 months (95% CI, 13-40). Predictors of increased survival in a multivariable analysis included age <65 years (P < .001), KPS ≥80 (P < .001), absence of extracranial metastases (P < .001), fewer BM at first SRS (≤3, P = .003), and targeted therapy (P = .005), whereas chemotherapy alone was associated with shorter survival (P = .04). In a subgroup of patients managed before 2016 (n = 264), 38 (14%) were long-term survivors (≥5 years), of which 16% required no active cancer treatment (systemic or brain) for ≥3 years by the end of their follow-up. CONCLUSION/CONCLUSIONS:Long-term survival in patients with brain metastases from NSCLC is feasible in the current era of SRS when combined with the use of effective targeted therapeutics. Of those living ≥5 years, the chance for living with stable disease without the need for active treatment for ≥3 years was 16%.
PMID: 36722962
ISSN: 1524-4040
CID: 5420082

Causes of Death in Patients With Brain Metastases

Schnurman, Zane; Mashiach, Elad; Link, Katherine E; Donahue, Bernadine; Sulman, Erik; Silverman, Joshua; Golfinos, John G; Oermann, Eric Karl; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:Advances in targeted therapies and wider application of stereotactic radiosurgery (SRS) have redefined outcomes of patients with brain metastases. Under modern treatment paradigms, there remains limited characterization of which aspects of disease drive demise and in what frequencies. This study aims to characterize the primary causes of terminal decline and evaluate differences in underlying intracranial tumor dynamics in patients with metastatic brain cancer. These fundamental details may help guide management, patient counseling, and research priorities. METHODS:Using NYUMets-Brain-the largest, longitudinal, real-world, open data set of patients with brain metastases-patients treated at New York University Langone Health between 2012 and 2021 with SRS were evaluated. A review of electronic health records allowed for the determination of a primary cause of death in patients who died during the study period. Causes were classified in mutually exclusive, but collectively exhaustive, categories. Multilevel models evaluated for differences in dynamics of intracranial tumors, including changes in volume and number. RESULTS:Of 439 patients with end-of-life data, 73.1% died secondary to systemic disease, 10.3% died secondary to central nervous system (CNS) disease, and 16.6% died because of other causes. CNS deaths were driven by acute increases in intracranial pressure (11%), development of focal neurological deficits (18%), treatment-resistant seizures (11%), and global decline driven by increased intracranial tumor burden (60%). Rate of influx of new intracranial tumors was almost twice as high in patients who died compared with those who survived (P < .001), but there was no difference in rates of volume change per intracranial tumor (P = .95). CONCLUSION/CONCLUSIONS:Most patients with brain metastases die secondary to systemic disease progression. For patients who die because of neurological disease, tumor dynamics and cause of death mechanisms indicate that the primary driver of decline for many may be unchecked systemic disease with unrelenting spread of new tumors to the CNS rather than failure of local growth control.
PMID: 37255296
ISSN: 1524-4040
CID: 5543262

Quantitative Analysis of Parenchymal Effects and Flow of Large Arteriovenous Malformations Managed With Stereotactic Radiosurgery

Alzate, Juan Diego; Mashiach, Elad; Bernstein, Kenneth; De Nigris Vasconcellos, Fernando; Qu, Tanxia; Silverman, Joshua S; Shapiro, Maksim; Nelson, Peter K; Raz, Eytan; Riina, Howard A; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:Stereotactic radiosurgery (SRS) of larger arteriovenous malformations (AVM) is associated with an elevated incidence of adverse radiation effects (ARE). To date, volume-response and dose-response models have been used to predict such effects. To understand radiological outcomes and their hemodynamic effects on the regional brain. METHODS:A retrospective analysis was conducted at our institution using a prospective registry of patients managed between 2014 and 2020. We included patients with AVM with a nidus larger than 5 cc who received either single-session or volume-staged Gamma Knife radiosurgery. AVM volume changes, volumes of parenchymal response, and obliteration were analyzed and correlated with transit times and diameters of feeding arteries and draining veins. RESULTS:Sixteen patients underwent single-session SRS, and 9 patients underwent volume-staged SRS. The average AVM volume was 12.6 cc (5.5-23). The AVM locations were predominantly lobar (80%) and 17 (68%) were in critical locations. The mean margin dose was 17.2 Gy (15-21), and the median V12Gy was 25.5 cc. Fourteen (56%) AVMs had a transit time shorter than 1 second. The median vein-artery ratio (sum diameter of the veins/sum diameter of feeding arteries) was 1.63 (range, 0.60-4.19). Asymptomatic parenchymal effects were detected in 13 (52%) patients and were symptomatic in 4 (16%) patients. The median time to ARE was 12 months (95% CI 7.6-16.4). On univariate analysis, significant predictors of ARE were lower vein-artery ratio (P = .024), longer transit time (P = .05), higher mean dose (P = .028), and higher D95 (P = .036). CONCLUSION/CONCLUSIONS:Transit times and vessel diameters are valuable predictors of the subsequent parenchymal response after SRS. A more quantitative understanding of blood flow is critical for predicting the effects on the regional brain after AVM radiosurgery.
PMID: 37235978
ISSN: 1524-4040
CID: 5508662

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes

Benjamin, Carolina; Gurewitz, Jason; Nakamura, Aya; Mureb, Monica; Mullen, Reed; Pacione, Donato; Silverman, Joshua; Kondziolka, Douglas
BACKGROUND:Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. OBJECTIVE:To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. METHODS:We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. RESULTS:(range 1.56-25.31). The median margin dose was 16 Gy (range 12-18). The average percent decrease in tumor volume compared to pre-SRS volume was 55% on imaging at 1-2 months, 58% at 3-5 months, 64% at 6-8 months, and 57% at > 8 months. There were no adverse events immediately following SRS. Median corticosteroid use after SRS was 21 days. Median survival after radiosurgery was 15 months. CONCLUSION/CONCLUSIONS:Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).
PMID: 36702970
ISSN: 0942-0940
CID: 5419722

How many brain metastases can be treated with stereotactic radiosurgery before the radiation dose delivered to normal brain tissue rivals that associated with standard whole brain radiotherapy?

Becker, Stewart J; Lipson, Evan J; Jozsef, Gabor; Molitoris, Jason K; Silverman, Joshua S; Presser, Joseph; Kondziolka, Douglas
INTRODUCTION/BACKGROUND:Clinical trial data comparing outcomes after administration of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) to patients with brain metastases (BM) suggest that SRS better preserves cognitive function and quality of life without negatively impacting overall survival. Here, we estimate the maximum number of BM that can be treated using single and multi-session SRS while limiting the dose of radiation delivered to normal brain tissue to that associated with WBRT. METHODS:Multiple-tumor SRS was simulated using a Monte Carlo - type approach and a pre-calculated dose kernel method. Tumors with diameters ≤36 mm were randomly placed throughout the contoured brain parenchyma until the brain mean dose reached 3 Gy, equivalent to the radiation dose delivered during a single fraction of a standard course of WBRT (a total dose of 30 Gy in 10 daily fractions of 3 Gy). Distribution of tumor sizes, dose coverage, selectivity, normalization, and maximum dose data used in the simulations were based on institutional clinical metastases data. RESULTS:The mean number of tumors treated, mean volume of healthy brain tissue receiving > 12 Gy (V12) per tumor, and total tumor volume treated using mixed tumor size distributions were 12.7 ± 4.2, 2.2 cc, and 12.9 cc, respectively. Thus, we estimate that treating 12-13 tumors per day over 10 days would deliver the dose of radiation to healthy brain tissue typically associated with a standard course of WBRT. CONCLUSION/CONCLUSIONS:Although in clinical practice, treatment with SRS is often limited to patients with ≤15 BM, our findings suggest that many more lesions could be targeted while still minimizing the negative impacts on quality of life and neurocognition often associated with WBRT. Results from this in silico analysis require clinical validation.
PMID: 36628586
ISSN: 1526-9914
CID: 5434362

Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases

Chan, Michael; Tatter, Steven; Chiang, Veronica; Fecci, Peter; Strowd, Roy; Prabhu, Sujit; Hadjipanayis, Constantinos; Kirkpatrick, John; Sun, David; Sinicrope, Kaylyn; Mohammadi, Alireza M; Sevak, Parag; Abram, Steven; Kim, Albert H; Leuthardt, Eric; Chao, Samuel; Phillips, John; Lacroix, Michel; Williams, Brian; Placantonakis, Dimitris; Silverman, Joshua; Baumgartner, James; Piccioni, David; Laxton, Adrian
BACKGROUND/UNASSIGNED:Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. METHODS/UNASSIGNED:Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. RESULTS/UNASSIGNED:Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. CONCLUSIONS/UNASSIGNED:LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.
PMID: 37114245
ISSN: 2632-2498
CID: 5465532

Impact of Dosimetric Factors on Local Failure in Patients with Spine Metastasis after Stereotactic Body Radiotherapy: A Multi-Institutional Study [Meeting Abstract]

LeCompte, M C; Chen, X; Tseng, C L; Campbell, M; Balagamwala, E H; Hanan, J; Byun, D J; Silverman, J S; Foote, M C; Gatt, N; Mahadevan, A; Grimm, J; Redmond, K J
Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) is increasingly utilized in the treatment of spine metastasis. Preliminary data suggest that higher doses may improve local control, but may also increase risk of toxicity including vertebral compression fracture (VCF). Our single institution study recently found that a minimum dose of at least 21 Gy to 80% of planning target volume (PTV D80%) in 2 fractions was associated with higher risk of VCF. The purpose of this study is to assess this variable's relationship with local failure (LF) and VCF in an international, multi-institutional cohort. Materials/Methods: Patients with radiation naive solid tumor spine metastases treated with SBRT at 5 international institutions from 2010 - 2020 were included. Patients with surgical stabilization were excluded. LF was defined per spine response assessment in neuro-oncology criteria. Variables examined included spinal instability neoplastic score (SINS) factors and dosimetric/volumetric characteristics of radiation planning. All fractionation scheme doses were converted to 2-fraction equivalent doses (2fxED) using the linear quadratic model with an alpha/beta of 3 and used in analyses of PTV D80%. Univariate and multivariate Cox proportional hazard models for LF and VCF were constructed using the Fine and Gray competing risk method.
Result(s): 357 vertebral segments from 234 patients were treated with SBRT. Common primary tumor types were prostate (n = 50, 22%), non-small cell lung cancer (n = 42, 18%), breast (n = 35, 15%), and kidney (n = 25, 11%). Most (n = 199 pts, 242 segments) were treated with 2 or 3 fractions with a median prescription dose of 24 Gy or 27 Gy, respectively (range: 14-45 Gy in 1-5 fractions). Median follow was 21.1 months (0.6-88.4 mo). LF was 12.6% and 18.1% at 1- and 2-years, respectively. Variables associated with increased LF on univariate analysis were lower PTV D80% at 2fxED <=21 Gy (HR 0.36, 95% CI 0.20-0.65, p = 0.001) and lower prescription dose BED3 (HR 0.98 as continuous variable, CI 0.97-0.99, p = 0.03). On multivariate analysis, only PTV D80% at 2fxED <=21 Gy remained associated with increased risk of LF (HR 0.46, CI 0.24-0.85, p = 0.01). VCF incidence was low, at 4.2% and 6.7% at 1- and 2-years, respectively. Higher SINS was predictive of VCF (HR 1.22, CI 1.1-1.36, p <0.001). Patients with higher PTVD80% at 2fxED>21 Gy had a higher, albeit non-significant, risk of VCF (HR 3.30, CI 0.80-13.6, p = 0.10), consistent with our previous single institution study.
Conclusion(s): This multi-institutional, international study suggests that a PTV D80% at 2fxED <=21 Gy may increase the risk of LF, while >21 Gy may increase the likelihood of VCF. Prospective studies are needed to further explore this complex relationship and identify the dose/fractionation schedule that best balances local control with normal tissue toxicity including VCF.
ISSN: 1879-355x
CID: 5366232

Modern Hearing Preservation Outcomes After Vestibular Schwannoma Stereotactic Radiosurgery

Berger, Assaf; Alzate, Juan Diego; Bernstein, Kenneth; Mullen, Reed; McMenomey, Sean; Jethanemest, Daniel; Friedmann, David R; Smouha, Eric; Sulman, Erik P; Silverman, Joshua S; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.
PMID: 35973088
ISSN: 1524-4040
CID: 5299902