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Kathryn Beal

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Linda Osei Poku

Benjamin Ellingson

University of California, Los Angeles

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Rahadian Indarto Susilo

Universitas Airlangga Surabaya

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Papers by Kathryn Beal

Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging

Clinical Cancer Research, 2018

Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemorad... more Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival. Experimental Design: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival. Results: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases bac...

Phosphatidylinositol-3-Kinase Mutations Are Associated With Increased Local Failure in Brain Metastases Treated With Radiation

International journal of radiation oncology, biology, physics, Jan 15, 2018

To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local contr... more To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases. We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression. A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found t...

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent cal... more Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m/d once daily) with radiotherapy and TMZ 75 mg/m/d, followed by TMZ 150 mg to 200 mg/m 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic c...

Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases

Cancer, 2017

BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progres... more BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases. METHODS: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors). RESULTS: Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue. CONCLUSIONS: Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2017;

$Research paper thumbnail of Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma$

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma

International Journal of Radiation Oncology*Biology*Physics, 2017

Purpose-It has been reported previously that the combination of bevacizumab with hypofractionated... more Purpose-It has been reported previously that the combination of bevacizumab with hypofractionated stereotactic re-irradiation (HFSR) with 30Gy (6GyX5 fractions) was safe and efficacious in recurrent glioblastomas and high-grade gliomas (HGG). Because most recurrences are local, developing intensified HFSR dosing schedules remains of interest. We hypothesized that in combination with bevacizumab, HFSR doses could be further escalated, and designed a prospective phase I trial to establish the maximum tolerated dose (MTD) of a 3-fraction HFSR delivered concomitantly with standard doses of bevacizumab. Materials and Methods-Patients with recurrent HGG with KPS ≥ 60, history of standard fractionated initial radiation, tumor volume at recurrence ≤ 40cc and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 Phase I dose escalation trial design was utilized, with dose-limiting toxicities (DLT) defined as any grade 3-5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every two weeks. HFSR was initiated after two bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy/fraction.

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment

Journal for ImmunoTherapy of Cancer, 2017

Background: Brain metastases are common in patients with metastatic melanoma. With increasing num... more Background: Brain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy. Methods: From an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy. Results: From January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively. Conclusions: Concurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.

AI-09 * Patterns of Salvage Treatment for High Grade Glioma in the Temozolomide Era

Neuro-Oncology, 2014

Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 23, 2017

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth fa... more Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastas...

Genomic Analysis of Exceptional Responders to Low-Dose Radiation Therapy Reveals Somatic Mutations in ATM

International Journal of Radiation Oncology*Biology*Physics, 2016

The paradigm for the palliative radiation treatment of bone metastases (mets) is evolving over ti... more The paradigm for the palliative radiation treatment of bone metastases (mets) is evolving over time. Equipoise with a single large fraction (fx) was suggested in 2004, and, in 2011, became the basis of ASTRO's consensus guidelines, but single and hypofractionated RT remain underutilized. Since then, new radiopharmaceuticals and stereotactic body RT (SBRT) have also become part of the treatment armamentarium. In 2016, NQF #1822 will address underutilization of hypofractionated RT for simple bone mets while presenting new definitions of simple and complicated mets. With this in mind, we assessed our institution's evolving treatment strategy and reviewed relevant NQF bone met criteria.

Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 6, 2016

High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secreta... more High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of trea...

Corticosteroids compromise survival in glioblastoma

Brain : a journal of neurology, May 28, 2016

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consis... more Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We appli...

$Research paper thumbnail of Clinical Outcomes of Patients With Limited Brain Metastases Treated With Hypofractionated Conformal Radiation Therapy$

Clinical Outcomes of Patients With Limited Brain Metastases Treated With Hypofractionated Conformal Radiation Therapy

International Journal of Radiation Oncology*Biology*Physics, 2015

was reported in 30% of patients with only three patients (43%) requiring narcotics or short-cours... more was reported in 30% of patients with only three patients (43%) requiring narcotics or short-course steroids. There was no evidence of vertebral body fracture in any patient that achieved local control in the treated area. Conclusion: Spine stereotactic radiosurgery for thyroid metastases as a primary or adjuvant/salvage therapy is well-tolerated and yields high rates of local control. To our knowledge, this is the first study focusing on this modality for metastatic thyroid cancer patients only.

Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases

Journal of Neuro-Oncology, 2015

Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasional... more Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasionally associated with serious neurologic sequelae. Here, we investigated the incidence of and clinical variables associated with the development of radionecrosis and related radiographic changes after SRS for brain metastases in a cohort of patients with long-term follow up. 271 brain metastases treated with single-fraction linear accelerator-based SRS were analyzed. Radionecrosis was diagnosed either pathologically or radiographically. Univariate and multivariate Cox regression was performed to determine the association between radionecrosis and clinical factors available prior to treatment planning. After median follow up of 17.2 months, radionecrosis was observed in 70 (25.8 %) lesions, including 47 (17.3 %) symptomatic cases. 22 of 70 cases (31.4 %) were diagnosed pathologically and 48 (68.6 %) were diagnosed radiographically. The actuarial incidence of radionecrosis was 5.2 % at 6 months, 17.2 % at 12 months and 34.0 % at 24 months. On univariate analysis, radionecrosis was associated with maximum tumor diameter (HR 3.55, p < 0.001), prior whole brain radiotherapy (HR 2.21, p = 0.004), prescription dose (HR 0.56, p = 0.02

Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

International journal of radiation oncology, biology, physics, Jan 5, 2015

Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown ... more Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associate...

Survival of patients treated with radiation therapy for anaplastic astrocytoma

Radiology and Oncology, 2014

Background. Anaplastic astrocytoma (AA) represents 7% of primary brain tumors in adults. Patient-... more Background. Anaplastic astrocytoma (AA) represents 7% of primary brain tumors in adults. Patient-, tumor-, and treatment-related factors are thought to be predictive of survival. We retrospectively assessed the association of patient-, tumor-, and treatment-related factors with survival in AA treated with radiotherapy (RT) at our institution. Patients and methods. Medical records of patients with AA treated with RT between 1987 and 2007 were reviewed. Patient-, tumor-, and treatment-related variables were recorded and used to assign patients to a Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) classification. First use of chemotherapy was recorded. Log-rank tests and Cox regression models were used to assess for an association of patient-, tumor- and treatment-related factors with survival. Results. One-hundred twenty-six patients were eligible for study. Median age, Karnofsky performance status, and duration of symptoms were 43 years, 90, and 8 weeks. Me...

Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery

International journal of radiation oncology, biology, physics, 2014

With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patient... more With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone. We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE). The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P=.02), triple-negative (TN) disease (HR=2.0, P=.006), and active extracranial...

$Research paper thumbnail of Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma$

Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma

Clinical cancer research : an official journal of the American Association for Cancer Research, 2014

Bevacizumab is associated with decreased vascular permeability that allows for more aggressive ra... more Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma tran...

Ipilimumab and whole brain radiation therapy for melanoma brain metastases

Journal of Neuro-Oncology, 2014

Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor... more Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans posttreatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatmentrelated toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.

Transcriptional diversity of long-term glioblastoma survivors

Neuro-Oncology, 2014

Background. Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However... more Background. Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM. Methods. We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival .48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs. Results. The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n ¼ 2), neural (n ¼ 2), classical (n ¼ 2), and mesenchymal (n ¼ 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs. Conclusions. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.

Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery

Neuro-Oncology, 2013

Background. Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic... more Background. Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic radiosurgery (SRS) that can result in progressive neurologic decline. Currently, steroids are the standard of care treatment for brain RN despite their adverse effect profile and limited efficacy. The purpose of this study was to evaluate the treatment efficacy of cerebral RN to bevacizumab in patients with brain metastases previously treated with SRS. Methods. We retrospectively reviewed 14 lesions in 11 patients treated with bevacizumab for brain RN secondary to SRS for their brain metastases. Steroid dosing, RN-associated symptoms, and magnetic resonance imaging (MRI) scans were examined before, during, and after bevacizumab administration. Results. Of the 11 patients included, 6 had metastatic non-small cell lung cancer, and 5 had metastatic breast cancer. The mean percentage decrease in RN volume seen on T1 post-Gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI at first follow-up, at a mean of 26 days (range, 15-43 days), was 64.4% and 64.3%, respectively. MRI changes were sustained on follow-up MRI scans, obtained at a mean of 33 days (range, 7-58 days) after bevacizumab discontinuation. After bevacizumab treatment, all patients initially receiving steroids had a reduction in steroid requirement, and all but one had an improvement in or stability of RN-associated symptoms. No patients experienced intratumoral bleeds or other adverse effects related to their bevacizumab treatment. Conclusions. Bevacizumab is effective and safe for the treatment of RN after SRS for brain metastasis. In this context, bevacizumab offers symptomatic relief, a reduction in steroid requirement, and a dramatic radiographic response.

Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging

Clinical Cancer Research, 2018

Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemorad... more Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival. Experimental Design: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival. Results: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases bac...

Phosphatidylinositol-3-Kinase Mutations Are Associated With Increased Local Failure in Brain Metastases Treated With Radiation

International journal of radiation oncology, biology, physics, Jan 15, 2018

To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local contr... more To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases. We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression. A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found t...

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent cal... more Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m/d once daily) with radiotherapy and TMZ 75 mg/m/d, followed by TMZ 150 mg to 200 mg/m 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic c...

Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases

Cancer, 2017

BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progres... more BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases. METHODS: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors). RESULTS: Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue. CONCLUSIONS: Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2017;

$Research paper thumbnail of Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma$

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma

International Journal of Radiation Oncology*Biology*Physics, 2017

Purpose-It has been reported previously that the combination of bevacizumab with hypofractionated... more Purpose-It has been reported previously that the combination of bevacizumab with hypofractionated stereotactic re-irradiation (HFSR) with 30Gy (6GyX5 fractions) was safe and efficacious in recurrent glioblastomas and high-grade gliomas (HGG). Because most recurrences are local, developing intensified HFSR dosing schedules remains of interest. We hypothesized that in combination with bevacizumab, HFSR doses could be further escalated, and designed a prospective phase I trial to establish the maximum tolerated dose (MTD) of a 3-fraction HFSR delivered concomitantly with standard doses of bevacizumab. Materials and Methods-Patients with recurrent HGG with KPS ≥ 60, history of standard fractionated initial radiation, tumor volume at recurrence ≤ 40cc and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 Phase I dose escalation trial design was utilized, with dose-limiting toxicities (DLT) defined as any grade 3-5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every two weeks. HFSR was initiated after two bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy/fraction.

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment

Journal for ImmunoTherapy of Cancer, 2017

Background: Brain metastases are common in patients with metastatic melanoma. With increasing num... more Background: Brain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy. Methods: From an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy. Results: From January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively. Conclusions: Concurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.

AI-09 * Patterns of Salvage Treatment for High Grade Glioma in the Temozolomide Era

Neuro-Oncology, 2014

Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 23, 2017

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth fa... more Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastas...

Genomic Analysis of Exceptional Responders to Low-Dose Radiation Therapy Reveals Somatic Mutations in ATM

International Journal of Radiation Oncology*Biology*Physics, 2016

The paradigm for the palliative radiation treatment of bone metastases (mets) is evolving over ti... more The paradigm for the palliative radiation treatment of bone metastases (mets) is evolving over time. Equipoise with a single large fraction (fx) was suggested in 2004, and, in 2011, became the basis of ASTRO's consensus guidelines, but single and hypofractionated RT remain underutilized. Since then, new radiopharmaceuticals and stereotactic body RT (SBRT) have also become part of the treatment armamentarium. In 2016, NQF #1822 will address underutilization of hypofractionated RT for simple bone mets while presenting new definitions of simple and complicated mets. With this in mind, we assessed our institution's evolving treatment strategy and reviewed relevant NQF bone met criteria.

Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 6, 2016

High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secreta... more High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of trea...

Corticosteroids compromise survival in glioblastoma

Brain : a journal of neurology, May 28, 2016

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consis... more Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We appli...

$Research paper thumbnail of Clinical Outcomes of Patients With Limited Brain Metastases Treated With Hypofractionated Conformal Radiation Therapy$

Clinical Outcomes of Patients With Limited Brain Metastases Treated With Hypofractionated Conformal Radiation Therapy

International Journal of Radiation Oncology*Biology*Physics, 2015

was reported in 30% of patients with only three patients (43%) requiring narcotics or short-cours... more was reported in 30% of patients with only three patients (43%) requiring narcotics or short-course steroids. There was no evidence of vertebral body fracture in any patient that achieved local control in the treated area. Conclusion: Spine stereotactic radiosurgery for thyroid metastases as a primary or adjuvant/salvage therapy is well-tolerated and yields high rates of local control. To our knowledge, this is the first study focusing on this modality for metastatic thyroid cancer patients only.

Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases

Journal of Neuro-Oncology, 2015

Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasional... more Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasionally associated with serious neurologic sequelae. Here, we investigated the incidence of and clinical variables associated with the development of radionecrosis and related radiographic changes after SRS for brain metastases in a cohort of patients with long-term follow up. 271 brain metastases treated with single-fraction linear accelerator-based SRS were analyzed. Radionecrosis was diagnosed either pathologically or radiographically. Univariate and multivariate Cox regression was performed to determine the association between radionecrosis and clinical factors available prior to treatment planning. After median follow up of 17.2 months, radionecrosis was observed in 70 (25.8 %) lesions, including 47 (17.3 %) symptomatic cases. 22 of 70 cases (31.4 %) were diagnosed pathologically and 48 (68.6 %) were diagnosed radiographically. The actuarial incidence of radionecrosis was 5.2 % at 6 months, 17.2 % at 12 months and 34.0 % at 24 months. On univariate analysis, radionecrosis was associated with maximum tumor diameter (HR 3.55, p < 0.001), prior whole brain radiotherapy (HR 2.21, p = 0.004), prescription dose (HR 0.56, p = 0.02

Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

International journal of radiation oncology, biology, physics, Jan 5, 2015

Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown ... more Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associate...

Survival of patients treated with radiation therapy for anaplastic astrocytoma

Radiology and Oncology, 2014

Background. Anaplastic astrocytoma (AA) represents 7% of primary brain tumors in adults. Patient-... more Background. Anaplastic astrocytoma (AA) represents 7% of primary brain tumors in adults. Patient-, tumor-, and treatment-related factors are thought to be predictive of survival. We retrospectively assessed the association of patient-, tumor-, and treatment-related factors with survival in AA treated with radiotherapy (RT) at our institution. Patients and methods. Medical records of patients with AA treated with RT between 1987 and 2007 were reviewed. Patient-, tumor-, and treatment-related variables were recorded and used to assign patients to a Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) classification. First use of chemotherapy was recorded. Log-rank tests and Cox regression models were used to assess for an association of patient-, tumor- and treatment-related factors with survival. Results. One-hundred twenty-six patients were eligible for study. Median age, Karnofsky performance status, and duration of symptoms were 43 years, 90, and 8 weeks. Me...

Outcomes and prognostic factors in women with 1 to 3 breast cancer brain metastases treated with definitive stereotactic radiosurgery

International journal of radiation oncology, biology, physics, 2014

With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patient... more With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone. We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE). The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P=.02), triple-negative (TN) disease (HR=2.0, P=.006), and active extracranial...

$Research paper thumbnail of Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma$

Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma

Clinical cancer research : an official journal of the American Association for Cancer Research, 2014

Bevacizumab is associated with decreased vascular permeability that allows for more aggressive ra... more Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma tran...

Ipilimumab and whole brain radiation therapy for melanoma brain metastases

Journal of Neuro-Oncology, 2014

Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor... more Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans posttreatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatmentrelated toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.

Transcriptional diversity of long-term glioblastoma survivors

Neuro-Oncology, 2014

Background. Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However... more Background. Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM. Methods. We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival .48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs. Results. The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n ¼ 2), neural (n ¼ 2), classical (n ¼ 2), and mesenchymal (n ¼ 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs. Conclusions. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.

Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery

Neuro-Oncology, 2013

Background. Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic... more Background. Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic radiosurgery (SRS) that can result in progressive neurologic decline. Currently, steroids are the standard of care treatment for brain RN despite their adverse effect profile and limited efficacy. The purpose of this study was to evaluate the treatment efficacy of cerebral RN to bevacizumab in patients with brain metastases previously treated with SRS. Methods. We retrospectively reviewed 14 lesions in 11 patients treated with bevacizumab for brain RN secondary to SRS for their brain metastases. Steroid dosing, RN-associated symptoms, and magnetic resonance imaging (MRI) scans were examined before, during, and after bevacizumab administration. Results. Of the 11 patients included, 6 had metastatic non-small cell lung cancer, and 5 had metastatic breast cancer. The mean percentage decrease in RN volume seen on T1 post-Gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI at first follow-up, at a mean of 26 days (range, 15-43 days), was 64.4% and 64.3%, respectively. MRI changes were sustained on follow-up MRI scans, obtained at a mean of 33 days (range, 7-58 days) after bevacizumab discontinuation. After bevacizumab treatment, all patients initially receiving steroids had a reduction in steroid requirement, and all but one had an improvement in or stability of RN-associated symptoms. No patients experienced intratumoral bleeds or other adverse effects related to their bevacizumab treatment. Conclusions. Bevacizumab is effective and safe for the treatment of RN after SRS for brain metastasis. In this context, bevacizumab offers symptomatic relief, a reduction in steroid requirement, and a dramatic radiographic response.