scholarly journals NIMG-17. VALIDATION OF DIFFUSION MRI AS AN IMAGING BIOMARKER FOR BEVACIZUMAB THERAPY IN RECURRENT GLIOBLASTOMA IN A RANDOMIZED PHASE III TRIAL OF BEVACIZUMAB WITH OR WITHOUT VB-111 (GLOBE)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii150-ii150
Author(s):  
Benjamin Ellingson ◽  
Timothy Cloughesy ◽  
Chencai Wang ◽  
Kunal Patel ◽  
Catalina Raymond ◽  
...  
Keyword(s):  
Diffusion Mri ◽  
Tumor Volume ◽  
Univariate Analysis ◽  
Gaussian Model ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Phase Ii Trials ◽  
Anti Vegf

Abstract BACKGROUND Evidence from independent single center as well as multicenter phase II trials have suggested diffusion MRI is a strong predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF monotherapy, but not systemic chemotherapies or combination therapies with anti-VEGF agents. The current study builds on this body of evidence by evaluating these diffusion MR phenotypes in a large randomized phase III clinical trial. METHODS Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus bevacizumab in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. RESULTS Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed that patients with high ADCL had a significant survival advantage when pooling all patients (P=0.0006), as well as when examining the BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P< 0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. CONCLUSION Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111. Since ADCL was predictive of OS in combination BV+VB-111, results support the working hypothesis that co-administration of VB-111 with BV may block any VB-111 anti-tumor effect, whereas VB-111 monotherapy or priming may result in higher efficacy of VB-111.

scholarly journals Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma

2021 ◽  
Author(s):  
Benjamin M Ellingson ◽  
Kunal Patel ◽  
Chencai Wang ◽  
Catalina Raymond ◽  
Andrew Brenner ◽  
...  
Keyword(s):  
Diffusion Mri ◽  
Tumor Volume ◽  
Cox Regression ◽  
Controlled Trial ◽  
Univariate Analysis ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Phase Ii Trials

Abstract Background Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 um 2/ms) or low (< 1.24 um 2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. Results Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P=0.0006), as well as BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P<0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. Conclusion Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

scholarly journals Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials

2017 ◽  
Vol 23 (19) ◽  
pp. 5745-5756 ◽  
Author(s):  
Benjamin M. Ellingson ◽  
Elizabeth R. Gerstner ◽  
Marion Smits ◽  
Raymond Y. Huang ◽  
Rivka Colen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Survival Benefit ◽  
Diffusion Mri ◽  
Recurrent Glioblastoma ◽  
Phase Ii Trials ◽  
Anti Vegf ◽  
Overall Survival Benefit

scholarly journals Validation of diffusion MRI phenotypes for predicting response to bevacizumab in recurrent glioblastoma: post-hoc analysis of the EORTC-26101 trial

2020 ◽  
Vol 22 (11) ◽  
pp. 1667-1676
Author(s):  
Marianne Schell ◽  
Irada Pflüger ◽  
Gianluca Brugnara ◽  
Fabian Isensee ◽  
Ulf Neuberger ◽  
...  
Keyword(s):  
Phase Ii ◽  
Diffusion Mri ◽  
Cox Regression ◽  
Threshold Model ◽  
Prognostic Significance ◽  
Predictive Ability ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Imaging Biomarker ◽  
Molecular Characteristics

Abstract Background This study validated a previously described diffusion MRI phenotype as a potential predictive imaging biomarker in patients with recurrent glioblastoma receiving bevacizumab (BEV). Methods A total of 396/596 patients (66%) from the prospective randomized phase II/III EORTC-26101 trial (with n = 242 in the BEV and n = 154 in the non-BEV arm) met the inclusion criteria with availability of anatomical and diffusion MRI sequences at baseline prior treatment. Apparent diffusion coefficient (ADC) histograms from the contrast-enhancing tumor volume were fitted to a double Gaussian distribution and the mean of the lower curve (ADClow) was used for further analysis. The predictive ability of ADClow was assessed with biomarker threshold models and multivariable Cox regression for overall survival (OS) and progression-free survival (PFS). Results ADClow was associated with PFS (hazard ratio [HR] = 0.625, P = 0.007) and OS (HR = 0.656, P = 0.031). However, no (predictive) interaction between ADClow and the treatment arm was present (P = 0.865 for PFS, P = 0.722 for OS). Independent (prognostic) significance of ADClow was retained after adjusting for epidemiological, clinical, and molecular characteristics (P ≤ 0.02 for OS, P ≤ 0.01 PFS). The biomarker threshold model revealed an optimal ADClow cutoff of 1241*10–6 mm2/s for OS. Thereby, median OS for BEV-patients with ADClow ≥ 1241 was 10.39 months versus 8.09 months for those with ADClow < 1241 (P = 0.004). Similarly, median OS for non-BEV patients with ADClow ≥ 1241 was 9.80 months versus 7.79 months for those with ADClow < 1241 (P = 0.054). Conclusions ADClow is an independent prognostic parameter for stratifying OS and PFS in patients with recurrent glioblastoma. Consequently, the previously suggested role of ADClow as predictive imaging biomarker could not be confirmed within this phase II/III trial.

scholarly journals Quantification of contrast-uptake as imaging biomarker for disease progression of renal cell carcinoma after tumor ablation

2020 ◽  
Vol 61 (12) ◽  
pp. 1708-1716
Author(s):  
Bruno R Tegel ◽  
Steffen Huber ◽  
Lynn J Savic ◽  
MingDe Lin ◽  
Bernhard Gebauer ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Volume ◽  
Cox Regression ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Secondary Outcome ◽  
Tumor Diameter ◽  
Renal Metastases

Background The prognosis of patients with renal cell carcinoma (RCC) depends greatly on the presence of extra-renal metastases. Purpose To investigate the value of total tumor volume (TTV) and enhancing tumor volume (ETV) as three-dimensional (3D) quantitative imaging biomarkers for disease aggressiveness in patients with RCC. Material and Methods Retrospective, HIPAA-compliant, IRB-approved study including 37 patients with RCC treated with image-guided thermal ablation during 2007–2015. TNM stage, RENAL Nephrometry Score, largest tumor diameter, TTV, and ETV were assessed on cross-sectional imaging at baseline and correlated with outcome measurements. The primary outcome was time-to-occurrence of extra-renal metastases and the secondary outcome was progression-free survival (PFS). Correlation was assessed using a Cox regression model and differences in outcomes were shown by Kaplan–Meier plots with significance and odds ratios (OR) calculated by Log-rank test/generalized Wilcoxon and continuity-corrected Woolf logit method. Results Patients with a TTV or ETV > 5 cm3 were more likely to develop distant metastases compared to patients with TTV (OR 6.69, 95% confidence interval [CI] 0.33–134.4, P=0.022) or ETV (OR 8.48, 95% CI 0.42–170.1, P=0.016) < 5 cm3. Additionally, PFS was significantly worse in patients with larger ETV ( P = 0.039; median PFS 51.87 months vs. 69.97 months). In contrast, stratification by median value of the established, caliper-based measurements showed no significant correlation with outcome parameters. Conclusion ETV, as surrogate of lesion vascularity, is a sensitive imaging biomarker for occurrence of extra-renal metastatic disease and PFS in patients with RCC.

Experience With Bevacizumab in the Management of Epithelial Ovarian Cancer

2007 ◽  
Vol 25 (20) ◽  
pp. 2902-2908 ◽  
Author(s):  
Robert A. Burger
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Single Agent ◽  
Safety Data ◽  
Phase Iii ◽  
Primary Therapy ◽  
Phase Ii Trials ◽  
Anti Vegf ◽  
Taxane Chemotherapy

Müllerian duct adenocarcinomas, in particular epithelial ovarian cancers, continue to represent a major source of female cancer-related morbidity and mortality, despite advances in surgical management and innovations in cytotoxic chemotherapy. Angiogenesis-targeted therapy seems to be appropriate for exploration in these disease processes based on a wealth of evidence from preclinical and molecular epidemiology studies. Bevacizumab is a prototypical agent neutralizing vascular endothelial growth factor (VEGF), a critical angiogenic promoter related to tumor progression, malignant effusions, and prognosis in ovarian cancer. Phase II trials have demonstrated the activity of bevacizumab as a single agent and in combination with other modalities such as low-dose metronomic cyclophosphamide. Historical studies have supported these observations. Unique toxicities have been ascribed to the administration of bevacizumab and other anti-VEGF molecules for patients with this disease and other solid tumors. Although most of these toxicities (such as proteinuria, hypertension, and bleeding) are generally mild, and are either self-limiting or controllable, other adverse effects, though uncommon, may be serious (these include arterial thromboembolism, wound healing complications, and GI perforation or fistulae). Phase III trials are now in progress to determine the role of this drug in primary therapy as an adjunct to platinum-taxane chemotherapy. This article reviews the background and rationale for anti-VEGF therapy of ovarian cancer, summarizes efficacy and safety data from phase II trials and historical studies of bevacizumab in this disease, introduces the implementation of bevacizumab in phase III front-line trials, examines controversial aspects related to anti-VEGF therapy, and proposes future directions regarding bevacizumab and other angiogenic growth factor–targeted therapeutics.

scholarly journals NIMG-72. PROGNOSTIC VALUE OF [18F]-FDG POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH RECURRENT GLIOBLASTOMA RECEIVING BEVACIZUMAB

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi177-vi178
Author(s):  
Maya Graham ◽  
Simone Krebs ◽  
Tejus Bale ◽  
Kwaku Domfe ◽  
Stephanie Lobaugh ◽  
...  
Keyword(s):  
Overall Survival ◽  
Fdg Pet ◽  
Prognostic Value ◽  
Antiangiogenic Therapy ◽  
Univariate Analysis ◽  
Standardized Uptake Value ◽  
Recurrent Glioblastoma ◽  
Imaging Biomarker ◽  
Uptake Pattern ◽  
18F Fdg

Abstract BACKGROUND Bevacizumab is used extensively for the treatment of recurrent glioblastoma, and its modification of contrast-enhanced MRI creates a need for alternate prognostic read-outs. We sought to determine the prognostic value of [18F]-FDG (FDG) PET in glioblastoma patients performed during treatment with bevacizumab. METHODS We performed an institutional review board approved retrospective study on patients who underwent FDG PET within 4 weeks of a dose of bevacizumab for recurrent glioblastoma. Volumes of interest were placed over one reference lesion as defined by MRI. Maximum standardized uptake value (SUVmax) and peak standardized uptake value (SUVpeak) in this volume of interest were measured on PET, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and lesion-to-normal contralateral white matter ratios (SUVmax/cWM) were calculated. In addition, tumors were divided into 2 groups based on qualitative uptake pattern: (i) FDG non-avid and (ii) FDG avid. Statistical impact of PET parameters on overall survival (OS) was assessed, as was histopathological correlate of PET findings for patients with pathology available within 3 months of PET. RESULTS 31 patients were included. Qualitative uptake pattern was significantly associated with OS (p = 0.005), with a median OS of 9.7 months in FDG non-avid patients versus 4.5 months in FDG avid patients. In univariate analysis, SUVmax, SUVpeak and T/N ratio were also significantly associated with OS (p < 0.001). Dichotomizing our sample using a SUVmax cut-off of 15.3 was also predictive of OS (adjusted p = 0.05). Pathology was available for 7 patients (22.6%) and confirmed PET findings. CONCLUSION FDG PET is a promising imaging biomarker to predict overall survival in recurrent glioblastoma patients on chronic antiangiogenic therapy, offering a tool for guiding assessment of treatment response in this patient population.

scholarly journals CLRM-07. INCREASING EFFICIENCY IN EARLY PHASE MULTICENTER IMAGING BIOMARKER TRIALS: EMERGING STRATEGIES FROM THE GABLE (GLIOBLASTOMA ACCELERATED BIOMARKER LEARNING ENVIRONMENT) TRIAL

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv2-iv2
Author(s):  
Daniel Barboriak ◽  
Jon Steingrimsson ◽  
Constantine Gatsonis ◽  
David Schiff ◽  
Lawrence Kleinberg
Keyword(s):  
Learning Environment ◽  
Planning Process ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Evaluation Strategy ◽  
Multicenter Trials

Abstract Validated biomarkers that more accurately predict prognosis and/or measure disease burden in patients with high-grade gliomas would help triage which treatment strategies are most promising for evaluation in Phase III multicenter trials. Multicenter trials to evaluate imaging biomarkers in this group face particular challenges; these trials have historically been slow to accrue and have not recently succeeded in validating new imaging biomarkers useful in treatment development. Due to variability in image acquisition protocols, scanner hardware, image analysis, and interpretive schemes, promising results obtained in single centers are poor predictors of success in the multicenter setting. Multicenter preliminary data to support further evaluation of imaging biomarkers is rarely available. The need for more efficient trial designs that bring multicenter data earlier into the process of biomarker development has become increasingly clear. In this presentation, the planning process within ECOG-ACRIN’s Brain Tumor Working Group for a platform multicenter trial called GABLE (Glioblastoma Accelerated Biomarker Learning Environment trial) designed to evaluate biomarkers for distinguishing pseudoprogression from true progression in patients with newly diagnosed GBM is described. In our planning process, it was determined that efficiencies can be gained from evaluating multiple biomarker types in parallel rather than serially; in the context of the proposed trial, not only conventional imaging biomarkers but plasma biomarkers and radiomic biomarkers can be evaluated simultaneously. Patient tolerance limits the feasibility of evaluating multiple non-standard-of-care imaging biomarkers in parallel. For this group of biomarkers, a “fast-switching” serial evaluation strategy using multiple interim analyses was developed to triage out biomarkers unlikely to succeed in identifying patient groups with clinically significant differences in median survival. For biomarker triage, an endpoint of event-free survival (events of either death or NANO progression) was proposed. Simulations were used to evaluate alpha and beta error using this evaluation strategy.

scholarly journals Lessons From Anti–Vascular Endothelial Growth Factor and Anti–Vascular Endothelial Growth Factor Receptor Trials in Patients With Glioblastoma

2015 ◽  
Vol 33 (10) ◽  
pp. 1197-1213 ◽  
Author(s):  
Christine Lu-Emerson ◽  
Dan G. Duda ◽  
Kyrre E. Emblem ◽  
Jennie W. Taylor ◽  
Elizabeth R. Gerstner ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Antiangiogenic Therapy ◽  
Phase Iii ◽  
Imaging Biomarkers ◽  
Vascular Tumors ◽  
Antiangiogenic Agents ◽  
Vascular Endothelial ◽  
Anti Vegf ◽  
Endothelial Growth Factor

Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.

scholarly journals Bevacizumab for glioblastoma: current indications, surgical implications, and future directions

2014 ◽  
Vol 37 (6) ◽  
pp. E9 ◽  
Author(s):  
Brandyn A. Castro ◽  
Manish K. Aghi
Keyword(s):  
Extended Period ◽  
Neutralizing Antibody ◽  
Clinical Results ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Bevacizumab Treatment ◽  
Phase Iii Trials ◽  
Antiangiogenic Drug ◽  
Endothelial Growth Factor

Initial enthusiasm after promising Phase II trials for treating recurrent glioblastomas with the antiangiogenic drug bevacizumab—a neutralizing antibody targeting vascular endothelial growth factor—was tempered by recent Phase III trials showing no efficacy for treating newly diagnosed glioblastomas. As a result, there is uncertainty about the appropriate indications for the use of bevacizumab in glioblastoma treatment. There are also concerns about the effects of bevacizumab on wound healing that neurosurgeons must be aware of. In addition, biochemical evidence suggests a percentage of tumors treated with bevacizumab for an extended period of time will undergo transformation into a more biologically aggressive and invasive phenotype with a particularly poor prognosis. Despite these concerns, there remain numerous examples of radiological and clinical improvement after bevacizumab treatment, particularly in patients with recurrent glioblastoma with limited therapeutic options. In this paper, the authors review clinical results with bevacizumab for glioblastoma treatment to date, ongoing trials designed to address unanswered questions, current clinical indications based on existing data, neurosurgical implications of bevacizumab use in patients with glioblastoma, the current scientific understanding of the tumor response to short- and long-term bevacizumab treatment, and future studies that will need to be undertaken to enable this treatment to fulfill its therapeutic promise for glioblastoma.

scholarly journals SURG-13. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: A REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED SURGICAL COHORT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii206-ii206
Author(s):  
Hassan Fadel ◽  
Sameah Haider ◽  
Jacob Pawloski ◽  
Hesham Zakaria ◽  
Farhan Chaudhry ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Subgroup Analysis ◽  
Tumor Volume ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Survival Outcomes ◽  
Repeat Surgery ◽  
Laser Interstitial Thermal Therapy ◽  
Recurrent Gbm

Abstract INTRODUCTION Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection. METHODS A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. RESULTS A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p&lt; 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p&lt; 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort. CONCLUSION After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.

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