DCE-MRI Evaluation of 10 patients with brain metastases treated with RRx-001, a Myc inhibitor and a CD47 and PD-L1 downregulator, in a phase I/II trial called BRAINSTORM.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14509-e14509
Author(s):  
Michelle Miran Kim ◽  
Hemant Parmar ◽  
Madhava P Aryal ◽  
Scott Caroen ◽  
Theresa Devasia ◽  
...  
Keyword(s):  
Single Dose ◽  
Brain Metastases ◽  
Plasma Volume ◽  
Tumor Volume ◽  
Tumor Response ◽  
Phase 1 ◽  
Univariate Analysis ◽  
Whole Brain Radiotherapy ◽  
Dce Mri ◽  
Brain Radiotherapy

e14509 Background: In a Phase 1/2 trial called BRAINSTORM (NCT02215512) for brain metastases from any histology, quantitative changes in perfusion MRI after administration of RRx-001, a mic inhibitor and CD47 and PD-L1 downregulator with vascular normalizing properties, were determined and correlated with response. Methods: Ten patients with 64 total lesions evaluable at baseline, 24 hours, and end of radiotherapy (RT) that participated in BRAINSTORM were subjected to a correlative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examination four days prior to the start of whole brain radiotherapy (WBRT) that evaluated Ktrans (capillary permeability) and Vp (plasma volume). The treatment comprised RRx-001 on Day -4, pre-WBRT then twice weekly during WBRT. Four dose levels were administered (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, and 27.5 mg/m2. Results: 10 patients underwent DCE-MRI scans and eight patients with 44 total evaluable lesions had available imaging at 1 month, and 6 patients with 29 total evaluable lesions had imaging at 4 months. On univariate analysis, only a decrease in 24-hour Vp from baseline after a single dose of RRx-001 was marginally associated with absolute tumor volume response 1 month after treatment (p-0.07). In a multivariate model, only Vp prior to therapy and 24-hour change in Vp were retained in the model after stepwise selection. A reduction in Vp 24 hours after RRx-001 (prior to WBRT) was associated with reduced tumor volume at 1 month (Estimate 0.88, 95% CI 0.37-1.40, p = 0.001) and 4 months (Estimate 1.51, 95% CI 0.58-2.43, p = 0.003). Likewise, a lower Vp prior to therapy was associated with reduced tumor volume at 1 month (Estimate 0.73, 95% CI 0.29-1.17, p = 0.002) and 4 months (Estimate 1.8, 95% CI 0.95-2.65, p = 0.0002), suggesting anti-angiogenic activity and early potential vascular normalization after a single dose of RRx-001 predictive of longer-term tumor response. Conclusions: RRx-001 induced a reduction in blood plasma volume, which was associated with tumor response and which suggests a vascular normalizing effect that merits further investigation in future planned studies. Clinical trial information: NCT02215512.

Identification of prognostic factors in patients with brain metastases: A review of 493 patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 11516-11516
Author(s):  
B. P. Baltalarli ◽  
D. Yalman ◽  
O. Akagündüz ◽  
Z. Ozsaran ◽  
Y. Anacak ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Whole Brain Radiotherapy ◽  
Late Toxicity ◽  
Female Gender ◽  
University Hospital ◽  
Rank Test ◽  
Brain Radiotherapy ◽  
Selection Of

11516 Background: Choice of treatment for an individual patient with brain metastases is based on a number of factors: number and localization of brain metastases, systemic tumor activity, performance score, and age are major determinants for selection of treatment modality. Future trials in patients with brain metastases depend on selection of patients with favorable prognosis to allow adequate long-term follow-up to draw conclusions about survival and late toxicity, further stressing the importance of prognostic parameters. Our aim is to report the outcome of patients with brain metastases from solid tumors treated with whole brain radiotherapy (WBRT) in a single institution and identify the prognostic subgroups who will benefit from treatment. Methods: The records of 493 patients with brain metastases who had been admitted for WBRT in the Department of Radiation Oncology in Ege University Hospital between January 1997 and December 2002 was retrospectively evaluated. WBRT at this institution comprised of parallel opposed lateral fields, dosed to the midplane in a cobalt 60 teletherapy device. Radiotherapy fractionation were 10 fr. × 3 Gy, 5 fr × 4 Gy and 2 fr. × 8 Gy. Survival was calculated using the Kaplan-Meier method. Cox regression modeling was used for multivariate analysis and prognostical factors were determined on the basis of log rank test (SPSS 10.00 version). Results: Clinical response evaluation revealed that 254 patients (51%) had response to tretament whereas 104 patients (21.1%) had stable response and the other 43 patients (8.7%) had progressive disease.The median survival was 3 months (1–62 months) and 6 months survival was 41% and one year survival was 19%. Univariate analysis revealed that prognostical factors for survival were younger age (age <57) (p=0.043), female gender (p=0.019) and operation (p=0.0004), and for multivariant analysis female gender (p=0.027) and operation were determined (p=0.000). Conclusion: The prognosticators for survival in this retrospective analysis for patients with brain metastases are age, gender and operation. These factors affecting survival must be taken into consideration when the therapeutic management is to be made. And they may allow better selection of individual treatments. No significant financial relationships to disclose.

scholarly journals Clinical outcomes in patients with brain metastases from breast cancer treated with single-session radiosurgery or whole brain radiotherapy

2016 ◽  
Vol 125 (Supplement_1) ◽  
pp. 26-30 ◽  
Author(s):  
Michael Mix ◽  
Rania Elmarzouky ◽  
Tracey O'Connor ◽  
Robert Plunkett ◽  
Dheerendra Prasad
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Median Survival ◽  
Tumor Volume ◽  
Whole Brain Radiotherapy ◽  
Metastatic Tumor ◽  
Whole Brain ◽  
Receptor Status ◽  
Brain Radiotherapy ◽  
Her 2

OBJECTIVEGamma Knife radiosurgery (GKRS) is used to treat brain metastases from breast cancer (BMB) as the sole treatment or in conjunction with tumor resection and/or whole brain radiotherapy (WBRT). This study evaluates outcomes in BMB based on treatment techniques and tumor biological features.METHODSThe authors reviewed all patients treated with BMB between 2004 and 2014. Patients were identified from a prospectively collected radiosurgery database and institutional tumor registry; 214 patients were identified. Data were collected from aforementioned sources and supplemented with chart review where needed. Independent radiological review was performed for all available brain imaging in those treated with GKRS. Survival analyses are reported using Kaplan-Meier estimates.RESULTSDuring the 10-year study period, 214 patients with BMB were treated; 23% underwent GKRS alone, 46% underwent a combination of GKRS and WBRT, and 31% underwent WBRT alone. Median survival after diagnosis of BMB in those treated with GKRS alone was 21 months, and in those who received WBRT alone it was 3 months. In those treated with GKRS plus WBRT, no significant difference in median survival was observed between those receiving WBRT upfront or in a salvage setting following GKRS (19 months vs 14 months, p = 0.63). The median survival of patients with total metastatic tumor volume of ≤ 7 cm3 versus > 7 cm3 was 20 months vs 7 months (p < 0.001). Human epidermal growth factor receptor-2 (Her-2) positively impacted survival after diagnosis of BMB (19 months vs 12 months, p = 0.03). Estrogen receptor status did not influence survival after diagnosis of BMB. No difference was observed in survival after diagnosis of BMB based on receptor status in those who received WBRT alone.CONCLUSIONSIn this single-institution series of BMB, the addition of WBRT to GKRS did not significantly influence survival, nor did the number of lesions treated with GKRS. Survival after the diagnosis of BMB was most strongly affected by Her-2 positivity and total metastatic tumor volume.

scholarly journals Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study

2015 ◽  
Vol 18 (3) ◽  
pp. 435-444 ◽  
Author(s):  
Esther J.J. Habets ◽  
Linda Dirven ◽  
Ruud G. Wiggenraad ◽  
Antoinette Verbeek-de Kanter ◽  
Geert J. Lycklama à Nijeholt ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Detrimental Effect ◽  
Tumor Volume ◽  
Whole Brain Radiotherapy ◽  
Neurocognitive Functioning ◽  
Brain Radiotherapy ◽  
Related Quality ◽  
Health Related ◽  
A Prospective Study

Abstract Background Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect on neurocognitive functioning and health-related quality of life (HRQoL) than whole-brain radiotherapy. To evaluate the impact of brain metastases and SRT on neurocognitive functioning and HRQoL, we performed a prospective study. Methods Neurocognitive functioning and HRQoL of 97 patients with brain metastases were measured before SRT and 1, 3, and 6 months after SRT. Seven cognitive domains were assessed. HRQoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and BN20 questionnaires. Neurocognitive functioning and HRQoL over time were analyzed with linear mixed models and stratified for baseline Karnofsky performance status (KPS), total metastatic volume, and systemic disease. Results Median overall survival of patients was 7.7 months. Before SRT, neurocognitive domain and HRQoL scores were lower in patients than in healthy controls. At group level, patients worsened in physical functioning and fatigue at 6 months, while other outcome parameters of HRQoL and cognition remained stable. KPS &lt; 90 and tumor volume &gt;12.6 cm3 were both associated with worse information processing speed and lower HRQoL scores over 6 months time. Intracranial tumor progression was associated with worsening of executive functioning and motor function. Conclusions Prior to SRT, neurocognitive functioning and HRQoL are moderately impaired in patients with brain metastases. Lower baseline KPS and larger tumor volume are associated with worse functioning. Over time, SRT does not have an additional detrimental effect on neurocognitive functioning and HRQoL, suggesting that SRT may be preferred over whole-brain radiotherapy.

scholarly journals NIMG-04. MRI EVALUATION OF THE EFFECT OF WHOLE BRAIN RADIOTHERAPY ON BRAIN METASTASIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii147-ii147
Author(s):  
William Crowe ◽  
Dawen Zhao ◽  
Zhongwei Zhang ◽  
Lulu Wang ◽  
John Bourland
Keyword(s):  
Brain Metastasis ◽  
Cytotoxic Effect ◽  
Tumor Volume ◽  
Whole Brain Radiotherapy ◽  
Whole Brain ◽  
Dce Mri ◽  
Brain Radiotherapy ◽  
Contrast Enhanced ◽  
Longitudinal Mri ◽  
Bbb Permeability

Abstract Poor prognosis of breast cancer brain metastasis partially results from the inability of therapeutics to penetrate the Blood-Brain-Barrier (BBB). Whole Brain Radiotherapy (WBRT) is standard-of-care for brain metastasis, however the early effects of fractionated WBRT on brain metastases have not been evaluated. Here, we applied longitudinal MRI to study WBRT’s effect on tumor volume, BBB permeability, and tumor-cell killing using anatomic, Dynamic Contrast Enhanced (DCE), and Diffusion-weighted (DW) MRI, evaluating tumor volume, permeability, and cytotoxic effect, respectively. The BCBM mouse model was established with left ventricle MDA-MB231-Br cell injection. MRI occurred before and 24h after 3 daily fractionated 4Gy WBRT (2.4Gy/min) or sham irradiation. In addition to anatomic MRI, DW MRI measured tissue ADC to study cytotoxic effect, and DCE MRI measured BBB permeability, quantified as the permeability variable Ktrans. Before treatment, T2-weighted images revealed hyperintense multifocal lesions in brains, and many had intact BBB indicated by no T1-w contrast-enhancement. WBRT tumors were smaller than sham irradiated tumors after 3 days (p&lt; 0.05), while no difference in the number of new lesions was observed. DW MRI demonstrated increased ADC in WBRT tumors (p&lt; 0.05), correlating well with elevated Caspase-3 staining of apoptotic cells. T1-w contrast enhanced images of tumors after treatment revealed no differences in the population of contrast-enhanced tumors between the WBRT and sham radiation groups. However, quantitative DCE MRI showed higher Ktrans in WBRT treated tumors relative to sham treated lesions, and an increase in Ktrans of WBRT tumors (p&lt; 0.05), despite high permeability heterogeneity both inter- and intra-tumorally, indicating remaining impermeable BBB. In addition to monitoring tumor volume, longitudinal MRI provided non-invasive assessments of temporal and spatial changes in cellularity and vascular permeability of brain metastasis in response to WBRT, which may prove to be useful for defining an ideal treatment window for potential combination BCBM treatments.

Prognostic factors and survival after whole-brain radiotherapy for initial brain metastases arising from non-small cell lung cancer

2021 ◽  
pp. 1-6
Author(s):  
Yukinori Okada ◽  
Mariko Kobayashi ◽  
Mio Shinozaki ◽  
Tatsuyuki Abe ◽  
Naoki Nakamura
Keyword(s):  
Prognostic Factors ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Gene Mutation ◽  
Stage Iv ◽  
Whole Brain Radiotherapy ◽  
Hazard Ratio ◽  
Small Cell Lung ◽  
Mutation Status ◽  
Brain Radiotherapy

Abstract Aim: To identify prognostic factors and investigate patient survival after whole-brain radiotherapy (WBRT) for initial brain metastases arising from non-small cell lung cancer (NSCLC). Methods: Patients diagnosed with NSCLC between 1 January 2010 and 30 September 2019, and who received WBRT upon first developing a brain metastasis, were investigated. Overall survival was determined as related to age, sex, duration between initial examination and brain metastasis detection, stage at the first examination, presence of metastases outside the brain, blood analysis findings, brain metastasis symptoms, radiotherapy dose and completion, imaging findings, therapeutic course of chemotherapy and/or radiation therapy, histological type, and gene mutation status. Results: Thirty-one consecutive patients (20 men and 11 women) with a mean age of 63·8 years and median survival of 129 days were included. Multivariate analysis with stepwise testing was performed to investigate differences in survival according to gene mutation status, lactate dehydrogenase (LDH) level, irradiation dose, WBRT completion and Stage status. Of these, a statistically significant difference in survival was observed in patients with gene mutation status (hazard ratio: 0·31, 95% CI: 0·11–0·86, p = 0·025), LDH levels <230 vs. ≥230 IU/L (hazard ratio: 4·08, 95% CI: 1·45–11·5, p < 0·01) received 30 Gy, 30 Gy/10 fractions to 35 Gy/14 fractions, and 37·5 Gy/15 fractions (hazard ratio: 0·26, 95% CI: 0·09–0·71, p < 0·01), and stage IV versus non-stage IV (hazard ratio: 0·13, 95 CI:0·02–0·64, p < 0·01) Findings: Gene mutation, LDH, radiation dose and Stage are prognostic factors for patients with initial brain metastases who are treated with WBRT.

scholarly journals A Dutch phase III randomized multicenter trial: whole brain radiotherapy vs. stereotactic radiotherapy for 4-10 brain metastases

2021 ◽  
Author(s):  
Dianne Hartgerink ◽  
Anna Bruynzeel ◽  
Danielle Eekers ◽  
Ans Swinnen ◽  
Coen Hurkmans ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Side Effects ◽  
Brain Metastases ◽  
Survival Rates ◽  
Whole Brain Radiotherapy ◽  
Phase Iii ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
One Year

Abstract Background The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. Methods Patients with 4 to 10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at three months post-treatment. Results The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range, 4-9) and the median total treatment volume was 13.0 cc 3 (range, 1.8-25.9 cc 3). QOL at three months decreased in the SRS group by 0.1 (SD=0.2), compared to 0.2 (SD=0.2) in the WBRT group (p=0.23). The actuarial one-year survival rates were 57% (SRS) and 31% (WBRT) (p=0.52). The actuarial one-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (p=0.22). Conclusion In patients with 4 to 10 BM, SRS alone resulted in one-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

scholarly journals Whole-brain radiotherapy in patients with brain metastases from melanoma

CNS Oncology ◽  
2014 ◽  
Vol 3 (6) ◽  
pp. 401-406 ◽  
Author(s):  
Macarena de la Fuente ◽  
Kathryn Beal ◽  
Richard Carvajal ◽  
Thomas J Kaley
Keyword(s):  
Brain Metastases ◽  
Whole Brain Radiotherapy ◽  
Whole Brain ◽  
Brain Radiotherapy
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