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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

Editorial Protons for Pediatric Ependymoma: Where Are We Now? [Comment]

Donahue, Bernadine; MacDonald, Shannon
PMID: 35294554
ISSN: 1523-5866
CID: 5182422

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

Berger, Assaf; Bernstein, Kenneth; Alzate, Juan Diego; Mullen, Reed; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Pavlick, Anna C; Gurewitz, Jason; Mureb, Monica; Mehnert, Janice; Madden, Kathleen; Palermo, Amy; Weber, Jeffrey S; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
PMID: 35665462
ISSN: 1573-7373
CID: 5248172

Survival and outcomes in patients with ≥ 25 cumulative brain metastases treated with stereotactic radiosurgery

Benjamin, Carolina Gesteira; Gurewitz, Jason; Kavi, Ami; Bernstein, Kenneth; Silverman, Joshua; Mureb, Monica; Donahue, Bernadine; Kondziolka, Douglas
OBJECTIVE:In the era in which more patients with greater numbers of brain metastases (BMs) are being treated with stereotactic radiosurgery (SRS) alone, it is critical to understand how patient, tumor, and treatment factors affect functional status and overall survival (OS). The authors examined the survival outcomes and dosimetry to critical structures in patients treated with Gamma Knife radiosurgery (GKRS) for ≥ 25 metastases in a single session or cumulatively over the course of their disease. METHODS:A retrospective analysis was conducted at a single institution. The institution's prospective Gamma Knife (GK) SRS registry was queried to identify patients treated with GKRS for ≥ 25 cumulative BMs between June 2013 and April 2020. Ninety-five patients were identified, and their data were used for analysis. Treatment plans for dosimetric analysis were available for 89 patients. Patient, tumor, and treatment characteristics were identified, and outcomes and OS were evaluated. RESULTS:The authors identified 1132 patients with BMs in their institutional registry. Ninety-five patients were treated for ≥ 25 cumulative metastases, resulting in a total of 3596 tumors treated during 373 separate treatment sessions. The median number of SRS sessions per patient was 3 (range 1-12 SRS sessions), with nearly all patients (n = 93, 98%) having > 1 session. On univariate analysis, factors affecting OS in a statistically significant manner included histology, tumor volume, tumor number, diagnosis-specific graded prognostic assessment (DS-GPA), brain metastasis velocity (BMV), and need for subsequent whole-brain radiation therapy (WBRT). The median of the mean WB dose was 4.07 Gy (range 1.39-10.15 Gy). In the top quartile for both the highest cumulative number and highest cumulative volume of treated metastases, the median of the mean WB dose was 6.14 Gy (range 4.02-10.15 Gy). Seventy-nine patients (83%) had all treated tumors controlled at last follow-up, reflecting the high and durable control rate. Corticosteroids for tumor- or treatment-related effects were prescribed in just over one-quarter of the patients. Of the patients with radiographically proven adverse radiation effects (AREs; 15%), 4 were symptomatic. Four patients required subsequent craniotomy for hemorrhage, progression, or AREs. CONCLUSIONS:In selected patients with a large number of cumulative BMs, multiple courses of SRS are feasible and safe. Together with new systemic therapies, the study results demonstrate that the achieved survival rates compare favorably to those of larger contemporary cohorts, while avoiding WBRT in the majority of patients. Therefore, along with the findings of other series, this study supports SRS as a standard practice in selected patients with larger numbers of BMs.
PMID: 34952524
ISSN: 1933-0693
CID: 5109192

The incidence and predictors of new brain metastases in patients with non-small cell lung cancer following discontinuation of systemic therapy

London, Dennis; Patel, Dev N; Donahue, Bernadine; Navarro, Ralph E; Gurewitz, Jason; Silverman, Joshua S; Sulman, Erik; Bernstein, Kenneth; Palermo, Amy; Golfinos, John G; Sabari, Joshua K; Shum, Elaine; Velcheti, Vamsidhar; Chachoua, Abraham; Kondziolka, Douglas
OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.
PMID: 34891140
ISSN: 1933-0693
CID: 5110502

Survival in Patients with >=5 Brain Metastases From Non-Small Cell Lung Cancer Treated With Upfront Stereotactic Radiosurgery

Gurewitz, J; Patel, D; Benjamin, C; Donahue, B R; Silverman, J; Mureb, M; Bernstein, K; Kondziolka, D
PURPOSE/OBJECTIVE(S): Multiple brain metastases (BM) from non-small cell lung cancer (NSCLC) historically has a dismal prognosis. Advances in systemic therapy for NSCLC have significantly improved survival, but the effect on prognosis in patients with NSCLC and BM is poorly understood. Stereotactic radiosurgery (SRS) may result in local control even with higher numbers of BM. We report survival outcomes of upfront SRS for >=5 BM from metastatic NSCLC. MATERIALS/METHODS: Review of our registry identified 177 patients treated for >=5 BM from NSCLC between 2012 and 2020, and did not undergo prior intracranial radiation or resection.
RESULT(S): Adenocarcinoma was found in 129 patients (73%). EGFR/ALK mutations were identified in 54 patients (31%). The median number of tumors at initial SRS were 8 (range 5-35). 121 patients (68%) were treated for 5-10 BM, 31 patients (18%) for 11-15 BM, and 25 patients (14%) for > 15 BM. The median overall survival (OS) from initial SRS for all patients was 15.1 months (95% CI 11.5-18.7). Survival at 1, 2, and 3 years was 57%, 39%, and 28% respectively. Adenocarcinoma was associated with improved survival compared to non-adenocarcinoma (P < 0.001), median OS 17.1 months (95% CI 11.4-22.9) and median OS 5.7 months (95% CI 2.8-8.6), respectively. Patients with EGFR/ALK mutations had a significantly greater survival time compared to those without (P=0.008), and median OS of 26.3 months (95% CI 19.1-33.6) versus 10.4 months (95% 6.2-14.6). Treatment of 5-10, 11-15, or > 15 tumors at initial GK were not associated with differences in survival (P=0.48). On multivariate analysis, survival benefit remained significant in patients with adenocarcinoma (HR 0.42, 95% CI 0.24-0.72, P=0.002), and patients with EGFR/ALK mutations (HR 0.58, 95% CI 0.37-0.91, P=0.02).
CONCLUSION(S): Patients treated with initial SRS for multiple BM from NSCLC in the modern era demonstrate longer survival as compared with historical reports. Adenocarcinoma subtype, particularly in the setting of EGFR/ALK mutation is associated with improved prognosis, even in patients with higher number of metastases. AUTHOR DISCLOSURE: J. Gurewitz: None. D. Patel: None. C. Benjamin: None. B.R. Donahue: None. J. Silverman: None. M. Mureb: None. K. Bernstein: None. D. Kondziolka: None.
ISSN: 1879-355x
CID: 5082202

Hippocampal sparing in patients receiving radiosurgery for ≥ 25 brain metastases

Kavi, Ami; Gurewitz, Jason; Benjamin, Carolina; Silverman, Joshua; Bernstein, Kenneth; Mureb, Monica; Oh, Cheongeun; Sulman, Erik P; Donahue, Bernadine; Kondziolka, Douglas
PURPOSE/OBJECTIVES/OBJECTIVE:To report our dosimetric analysis of the hippocampi (HC) and the incidence of perihippocampal tumor location in patients with≥25 brain metastases who received stereotactic radiosurgery (SRS) in single or multiple sessions. Materials/Methods Analysis of our prospective registry identified 89 patients treated with SRS for ≥ 25 brain metastases. HC avoidance regions (HA-region) were created on treatment planning MRIs by 5mm expansion of HC. Doses from each session were summed to calculate HC dose. The distribution of metastases relative to the HA-region and the HC was analyzed. RESULTS:Median number of tumors irradiated per patient was 33 (range 25-116) in a median of 3 (range1-12) sessions. Median bilateral HC Dmin (D100), D40, D50, Dmax, and Dmean (Gy) was 1.88, 3.94, 3.62, 16.6, and 3.97 for all patients, and 1.43, 2.99, 2.88, 5.64, and 3.07 for patients with tumors outside the HA-region. Multivariate linear regression showed that the median HC D40, D50, and Dmin were significantly correlated with the tumor number and tumor volume (p <0.001). Of the total3059 treated tumors,83 (2.7%) were located in the HA-region in 57% evaluable patients; 38 tumors (1.2%) abutted or involved the HC itself. CONCLUSIONS:Hippocampal dose, is higher in patients with tumors in the HA-region; however, even for patients with a high burden of intracranial disease and tumors located in the HA-regions, SRS affords hippocampal sparing. This is particularly relevant in light of our finding of eventual perihippocampal metastases in more than half of our patients.
PMID: 34052342
ISSN: 1879-0887
CID: 4890712

Primum Non Nocere: Not All Targetable Lesions Should Be Targeted [Letter]

Donahue, Bernadine; Cooper, Benjamin T
PMID: 33516434
ISSN: 1879-355x
CID: 4781772

Covert COVID-19: Cone Beam Computed Tomography Lung Changes in an Asymptomatic Patient Receiving Radiation Therapy

Youssef, Irini; Donahue, Bernadine; Flyer, Mark; Thompson, Sharon; Huang, Alice; Gallant, Fleure
Purpose/UNASSIGNED:COVID-19 profoundly affected the United States, with New York City rapidly becoming the epicenter of the disease. Patients with cancer represent a vulnerable population in this pandemic, with data suggesting a higher risk for severe events and unfavorable outcomes. Timely identification of COVID-19 in patients with cancer has been thwarted by the limited availability of outpatient testing for SARS-CoV-2. Chest computed tomography (CT) plays a major role in the identification of COVID-19 pneumonia, with radiologic hallmarks including bilateral, peripheral ground-glass opacities (GGOs) and consolidation. Patients with cancer undergoing radiation therapy (RT) commonly have daily cone beam computed tomography (CBCT) obtained for image-guided RT, and such imaging frequently includes the chest. Methods and Materials/UNASSIGNED:We retrospectively reviewed the CBCT scans of an initially asymptomatic patient undergoing image-guided RT for breast cancer who developed COVID-19 symptoms during the second week of RT. Lung windows of daily CBCT scans were reviewed with diagnostic radiology to survey for changes consistent with COVID-19. Diagnostic CT scans at the time of recovery were obtained and compared with the CBCTs. Results/UNASSIGNED:Five consecutive CBCT scans were retrospectively reviewed. Bilateral, peripheral GGOs were noted on the fourth and fifth CBCT scans in the 2 days before symptom onset. CBCT on the day of RT resumption demonstrated substantial worsening of the GGO compared with scans obtained during the asymptomatic phase. Diagnostic CTs demonstrated bilateral, peripheral GGOs and mediastinal lymphadenopathy, findings suggesting COVID-19 pneumonitis. Repeat diagnostic CT 3 days later showed improved pulmonary findings, and the patient resumed RT without incident. Conclusions/UNASSIGNED:Familiarity with typical CT changes of COVID-19 pneumonitis may allow for early detection in cancer patients undergoing CBCT for RT treatment. Prompt review of the lung windows is recommended to identify such changes, with the hope that presymptomatic diagnosis leads to expedited patient management, improved outcomes, and a reduction of inadvertent COVID-19 dissemination.
PMID: 32775781
ISSN: 2452-1094
CID: 4557182

Hippocampal Dosimetry In Patients Receiving Radiosurgery For >= 25 Brain Metastases: Implications For HA-WBRT [Meeting Abstract]

Kavi, A.; Gurewitz, J.; Benjamin, C.; Bernstein, K.; Silverman, J. S.; Donahue, B. R.; Kondziolka, D.
ISSN: 0360-3016
CID: 4686332