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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

Just Because You Can Does Not Mean That You Should… [Letter]

Silverman, Joshua S
PMID: 35427546
ISSN: 1879-355x
CID: 5202032

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

Predicting local failure of brain metastases after stereotactic radiosurgery with radiomics on planning MR images and dose maps

Wang, Hesheng; Xue, Jinyu; Qu, Tanxia; Bernstein, Kenneth; Chen, Ting; Barbee, David; Silverman, Joshua S; Kondziolka, Douglas
PURPOSE/OBJECTIVE:Stereotactic radiosurgery (SRS) has become an important modality in the treatment of brain metastases. The purpose of this study is to investigate the potential of radiomic features from planning magnetic resonance (MR) images and dose maps to predict local failure after SRS for brain metastases. MATERIALS/METHODS/METHODS:Twenty-eight patients who received Gamma Knife (GK) radiosurgery for brain metastases were retrospectively reviewed in this IRB-approved study. 179 irradiated tumors included 42 that locally failed within one-year follow-up. Using SRS tumor volumes, radiomic features were calculated on T1-weighted contrast-enhanced MR images acquired for treatment planning and planned dose maps. 125 radiomic features regarding tumor shape, dose distribution, MR intensities and textures were extracted for each tumor. Logistic regression with automatic feature selection was built to predict tumor progression from local control after SRS. Feature selection and model evaluation using receiver operating characteristic (ROC) curves were performed in a nested cross validation (CV) scheme. The associations between selected radiomic features and treatment outcomes were statistically assessed by univariate analysis. RESULTS:The logistic model with feature selection achieved ROC AUC of 0.82 ± 0.09 on 5-fold CV, providing 83% sensitivity and 70% specificity for predicting local failure. A total of 10 radiomic features including 1 shape feature, 6 MR images and 3 dose distribution features were selected. These features were significantly associated with treatment outcomes (p < 0.05). The model was validated on independent holdout data with an AUC of 0.78. CONCLUSIONS:Radiomic features from planning MR images and dose maps provided prognostic information in SRS for brain metastases. A model built on the radiomic features shows promise for early prediction of tumor local failure after treatment, potentially aiding in personalized care for brain metastases.
PMID: 34287940
ISSN: 2473-4209
CID: 5003892

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

Treatment of sellar metastases with gamma knife radiosurgery in patients with advanced cancer

Benjamin, Carolina; Ashayeri, Kimberly; Golfinos, John G; Placantonakis, Dimitris G; Silverman, Joshua; Kondziolka, Douglas
PURPOSE/OBJECTIVE:Metastases should be considered in a patient with a cancer history and a sellar/suprasellar lesion, as this diagnosis can change the management strategy in such patients. Once the diagnosis is established, stereotactic radiosurgery (SRS) can be a safe and effective approach for these patients. METHODS:This case series describes five patients with pituitary metastases managed with GKRS at a single institution, taken from our prospective registry. All patients had SRS using the Gamma Knife Perfexion or Icon (Elekta), according to our standard institutional protocol. The optic nerves and chiasm were contoured, and the plan was adjusted to restrict dose to the optic apparatus as necessary. The tumor margin doses delivered were 11 Gy, 12 Gy, 14 Gy, 18 Gy (3 sessions of 6 Gy), and 12 Gy at the 50% isodose line. RESULTS:In this series, all sellar metastases were treated successfully with good radiographic and clinical response. The histology of the tumors included endometrial, gastrointestinal, and lung adenocarcinomas. Typically, histology is taken into consideration when choosing the treatment dose, along with size and location. In these patients, however, the dose used for the sellar metastases was chosen primarily for visual safety. This was typically lower than the dose for brain metastases in other locations. CONCLUSION/CONCLUSIONS:SRS provides an alternative treatment approach for sellar/suprasellar metastases with excellent local control, symptom improvement and maintenance of systemic therapy as desired. As such, CNS failure is rarely the proximate cause of demise in pituitary metastases provided that endocrinopathies are recognized and managed appropriately.
PMID: 32860552
ISSN: 1573-7403
CID: 4587032

Full automation of spinal stereotactic radiosurgery and stereotactic body radiation therapy treatment planning using Varian Eclipse scripting

Teruel, Jose R; Malin, Martha; Liu, Elisa K; McCarthy, Allison; Hu, Kenneth; Cooper, Bejamin T; Sulman, Erik P; Silverman, Joshua S; Barbee, David
The purpose of this feasibility study is to develop a fully automated procedure capable of generating treatment plans with multiple fractionation schemes to improve speed, robustness, and standardization of plan quality. A fully automated script was implemented for spinal stereotactic radiosurgery/stereotactic body radiation therapy (SRS/SBRT) plan generation using Eclipse v15.6 API. The script interface allows multiple dose/fractionation plan requests, planning target volume (PTV) expansions, as well as information regarding distance/overlap between spinal cord and targets to drive decision-making. For each requested plan, the script creates the course, plans, field arrangements, and automatically optimizes and calculates dose. The script was retrospectively applied to ten computed tomography (CT) scans of previous cervical, thoracic, and lumbar spine SBRT patients. Three plans were generated for each patient - simultaneous integrated boost (SIB) 1800/1600 cGy to gross tumor volume (GTV)/PTV in one fraction; SIB 2700/2100 cGy to GTV/PTV in three fractions; and 3000 cGy to PTV in five fractions. Plan complexity and deliverability patient-specific quality assurance (QA) was performed using ArcCHECK with an Exradin A16 chamber inserted. Dose objectives were met for all organs at risk (OARs) for each treatment plan. Median target coverage was GTV V100% = 87.3%, clinical target volume (CTV) V100% = 95.7% and PTV V100% = 88.0% for single fraction plans; GTV V100% = 95.6, CTV V100% = 99.6% and PTV V100% = 97.2% for three fraction plans; and GTV V100% = 99.6%, CTV V100% = 99.1% and PTV V100% = 97.2% for five fraction plans. All plans (n = 30) passed patient-specific QA (>90%) at 2%/2 mm global gamma. A16 chamber dose measured at isocenter agreed with planned dose within 3% for all cases. Automatic planning for spine SRS/SBRT through scripting increases efficiency, standardizes plan quality and approach, and provides a tool for target coverage comparison of different fractionation schemes without the need for additional resources.
PMID: 32965754
ISSN: 1526-9914
CID: 4605772

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study

Rusthoven, Chad G; Yamamoto, Masaaki; Bernhardt, Denise; Smith, Derek E; Gao, Dexiang; Serizawa, Toru; Yomo, Shoji; Aiyama, Hitoshi; Higuchi, Yoshinori; Shuto, Takashi; Akabane, Atsuya; Sato, Yasunori; Niranjan, Ajay; Faramand, Andrew M; Lunsford, L Dade; McInerney, James; Tuanquin, Leonard C; Zacharia, Brad E; Chiang, Veronica; Singh, Charu; Yu, James B; Braunstein, Steve; Mathieu, David; Touchette, Charles J; Lee, Cheng-Chia; Yang, Huai-Che; Aizer, Ayal A; Cagney, Daniel N; Chan, Michael D; Kondziolka, Douglas; Bernstein, Kenneth; Silverman, Joshua S; Grills, Inga S; Siddiqui, Zaid A; Yuan, Justin C; Sheehan, Jason P; Cordeiro, Diogo; Nosaki, Kename; Seto, Takahashi; Deibert, Christopher P; Verma, Vivek; Day, Samuel; Halasz, Lia M; Warnick, Ronald E; Trifiletti, Daniel M; Palmer, Joshua D; Attia, Albert; Li, Benjamin; Cifarelli, Christopher P; Brown, Paul D; Vargo, John A; Combs, Stephanie; Kessel, Kerstin A; Rieken, Stefan; Patel, Samir; Guckenberger, Matthias; Andratschke, Nicolaus; Kavanagh, Brian D; Robin, Tyler P
Importance/UNASSIGNED:Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. Objective/UNASSIGNED:To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. Design, Setting, and Participants/UNASSIGNED:FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. Interventions/UNASSIGNED:SRS and WBRT for small cell lung cancer brain metastases. Main Outcomes and Measures/UNASSIGNED:Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. Results/UNASSIGNED:In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Conclusions and Relevance/UNASSIGNED:Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.
PMID: 32496550
ISSN: 2374-2445
CID: 4481022