[Show abstract][Hide abstract] ABSTRACT: Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.
International Journal of Oncology 02/2015; 46(5). DOI:10.3892/ijo.2015.2891 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the
Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology,
Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with
the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons,
biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National
Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged
to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this report is to describe the state of imaging techniques and technologies for detecting response of brain
tumors to treatment in the setting of multicenter clinical trials. Within currently used technologies, implementation of standardized
image acquisition and the use of volumetric estimates and subtraction maps are likely to help to improve tumor visualization,
delineation, and quantification. Upon further development, refinement, and standardization, imaging technologies such as diffusion
and perfusion MRI and amino acid PET may contribute to the detection of tumor response to treatment, particularly in specific
treatment settings. Over the next few years, new technologies such as 23Na MRI and CEST imaging technologies will be explored for their use in expanding the ability to quantitatively image tumor
response to therapies in a clinical trial setting.
[Show abstract][Hide abstract] ABSTRACT: Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability
of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus,
the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research.
[Show abstract][Hide abstract] ABSTRACT: PurposeTo investigate the efficacy and safety of three doses of gadobutrol and determine the minimum effective dose for contrast-enhanced MRI of the central nervous system (CNS). Materials and Methods
This was a Phase II, multicenter, double-blind, parallel-group controlled study in subjects referred for contrast-enhanced MRI of the CNS. Subjects were randomized to receive gadobutrol 0.03, 0.1, or 0.3mmol/kg body weight, and underwent unenhanced, gadobutrol-enhanced, and comparator-enhanced MRI scans. Three blinded readers assessed the images. Primary efficacy variables were number of lesions detected, border delineation, contrast enhancement, and internal morphology. ResultsOf the 229 randomized subjects, 173 were evaluated for efficacy. Clinically meaningful improvements in lesion border delineation, contrast enhancement, and internal morphology were observed for 0.1mmol/kg gadobutrol. Pair-wise comparisons of a composite score of the four primary variables showed the 0.1mmol/kg dose to be statistically superior to the 0.03mmol/kg dose (P=0.003). The 0.3mmol/kg dose showed no statistically significant difference with the 0.1mmol/kg dose. Twenty-two (9.8%) subjects reported at least one treatment-emergent adverse event (TEAE). No TEAE was reported at an incidence >3.5%. Conclusion
The 0.1mmol/kg dose of gadobutrol was effective and well tolerated for contrast-enhanced MRI of the CNS. J. Magn. Reson. Imaging 2014;39:410-418. (c) 2013 Wiley Periodicals, Inc.
Journal of Magnetic Resonance Imaging 02/2014; 39(2). DOI:10.1002/jmri.24180 · 3.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Chemoradiation (CRT) can significantly modify the radiographic appearance of malignant gliomas, especially within the immediate post-CRT period. Pseudoprogression (PsP) is an increasingly recognized phenomenon in this setting, and is thought to be secondary to increased permeability as a byproduct of the complex process of radiation-induced tissue injury, possibly enhanced by temozolomide. We sought to determine whether the addition of a vascular endothelial growth factor (VEGF) signaling inhibitor (cediranib) to conventional CRT had an impact on the frequency of PsP, by comparing two groups of patients with newly diagnosed glioblastoma before, during, and after CRT.
All patients underwent serial magnetic resonance imaging as part of institutional review board-approved clinical studies. Eleven patients in the control group received only chemoradiation, whereas 29 patients in the study group received chemoradiation and cediranib until disease progression or toxicity. Response assessment was defined according to Response Assessment in Neuro-Oncology criteria, and patients with enlarging lesions were classified into true tumor progressions (TTP) or PsP, based on serial radiographic follow-up.
Two patients in the study group (7%) showed signs of apparent early tumor progression, and both were subsequently classified as TTP. Six patients in the control group (54%) showed signs of apparent early tumor progression, and three were subsequently classified as TTP and three as PsP. The frequency of PsP was significantly higher in the control group.
Administration of a VEGF inhibitor during and after CRT modifies the expression of PsP by imaging.
The Oncologist 12/2013; 19(1). DOI:10.1634/theoncologist.2013-0101 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The investigation of metabolic pathways disturbed in isocitrate dehydrogenase (IDH) mutant tumors revealed that the hallmark metabolic alteration is the production of D-2-hydroxyglutarate (D-2HG). The biological impact of D-2HG strongly suggests that high levels of this metabolite may play a central role in propagating downstream the effects of mutant IDH, leading to malignant transformation of cells. Hence, D-2HG may be an ideal biomarker for both diagnosing and monitoring treatment response targeting IDH mutations. Magnetic resonance spectroscopy (MRS) is well suited to the task of noninvasive D-2HG detection, and there has been much interest in developing such methods. Here, we review recent efforts to translate methodology using MRS to reliably measure in vivo D-2HG into clinical research.
The Journal of clinical investigation 09/2013; 123(9):3659-63. DOI:10.1172/JCI67229 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Measurement of vessel caliber by magnetic resonance imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI termed vessel architectural imaging (VAI) that exploits an overlooked temporal shift in the magnetic resonance signal, forming the basis for vessel caliber estimation, and show how this phenomenon can reveal new information on vessel type and function not assessed by any other noninvasive imaging technique. We also show how this biomarker can provide new biological insights into the treatment of patients with cancer. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation and reduce vessel calibers in patients with recurrent glioblastomas and, more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies.
Nature medicine 08/2013; 73(8 Supplement). DOI:10.1038/nm.3289 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSEA randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS
Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans.ResultsThe primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION
This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.
[Show abstract][Hide abstract] ABSTRACT: Background: RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS). Methods: Of 123 enrolled patients, 107 had baseline and at least 1 posttreatment MRI. Two central neuroradiologists serially measured bidimensional (2D) and volumetric (3D) enhancement on postcontrast T1-weighted images and volume of FLAIR hyperintensity. Progression status on all posttreatment MRIs was determined using Macdonald and RANO imaging threshold criteria, with a third neuroradiologist adjudicating discrepancies of both progression occurrence and timing. For each MRI pulse sequence, Kaplan-Meier survival estimates and log-rank test were used to compare OS between cases with or without radiologic progression. Results: Radiologic progression occurred after 2 chemotherapy cycles (8 weeks) in 9 of 97 (9%), 9 of 73 (12%), and 11 of 98 (11%) 2D-T1, 3D-T1, and FLAIR cases, respectively, and 34 of 80 (43%), 21 of 58 (36%), and 37 of 79 (47%) corresponding cases after 4 cycles (16 weeks). Median OS among patients progressing at 8 or 16 weeks was significantly less than that among nonprogressors, as determined on 2D-T1 (114 vs 278 days and 214 vs 426 days, respectively; P <. 0001 for both) and 3D-T1 (117 vs 306 days [P <. 0001] and 223 vs 448 days [P =. 0003], respectively) but not on FLAIR (201 vs 276 days [P =. 38] and 303 vs 321 days [P =. 13], respectively).Conclusion
Early progression on 2D-T1 and 3D-T1, but not FLAIR MRI, after 8 and 16 weeks of anti-vascular endothelial growth factor therapy has highly significant prognostic value for OS in recurrent GBM.
[Show abstract][Hide abstract] ABSTRACT: Background
The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy.Methods
Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values.ResultsNAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression-free survival and 1-year survival.Conclusion
Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
RTOG 0625/ACRIN 6677 is a multi-center randomized phase II trial of bevacizumab (an anti-VEGF antibody) with irinotecan or temozolomide in recurrent GBM. The frequency of pseudoresponse in patients receiving VEGF blockade has raised concerns that radiologic response may not predict overall survival (OS). This study aimed to determine if progression on FLAIR or post-Gd 2D-T1 or 3D-T1 MRI after 2 or 4 anti-VEGF chemotherapy cycles (8 or 16 weeks) is predictive of OS.
METHOD AND MATERIALS
Of 123 enrolled patients (71 men, 52 women; ages 23-87 years, median 56), 107 had baseline and at least one post-treatment MRI (after every 2 treatment cycles or 8-week blocks). Two central readers serially measured bidimensional (2D) and volumetric (3D) enhancement on post-Gd T1-weighted images, and 3D FLAIR hyperintensity. Progression status on all post-treatment MRIs was determined using Macdonald criteria, with adjudication of discrepancies by a third reader. All readers had neuroradiology CAQ and were carefully trained and tested to reduce reader variance. Survival and censorship were defined with respect to enrollment date. Kaplan-Meier survival estimates and log-rank test were used to compare the overall survival for cases with or without radiologic progression.
Overall adjudication rates for time of progression were 43% (n=45) for 2D-T1, 42% (n=32) for 3D-T1, and 39% (n=42) for FLAIR. Excluding patients missing relevant scans or with precedent death, there was radiologic progression at 8 weeks in 9/97 (9%), 9/73 (12%), and 11/98 (11%) evaluable 2D-T1, 3D-T1, and FLAIR cases, respectively, and in 34/80 (43%), 21/58 (36%), and 37/79 (47%) corresponding cases at 16 weeks. The median OS (days) for patients with progression at 8 or 16 weeks was significantly less than that for patients without progression on 2D-T1 (114 vs. 278 and 214 vs. 426, p<0.0001 for both) and 3D-T1 (117 vs. 306, p<0.0001 and 223 vs. 448, p=0.0003), but not FLAIR (201 vs. 276, p=0.38 and 303 vs. 321, p=0.13).
Early progression on post-Gd 2D-T1 and 3D-T1, but not FLAIR MRI after 2 and 4 cycles (8 and 16 weeks) of anti-VEGF therapy has highly significant prognostic value for OS. Funded by NCI U01-CA080098 and U01-CA079778.
Early post-therapy progressive 2D-T1 and 3D-T1 enhancement may be a useful MRI biomarker for the failure of anti-VEGF therapy, permitting a timely switch to alternative trials when necessary.
Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
[Show abstract][Hide abstract] ABSTRACT: In this study, we investigated the structural plasticity of the contralesional motor network in ischemic stroke patients using diffusion magnetic resonance imaging (MRI) and explored a model that combines a MRI-based metric of contralesional network integrity and clinical data to predict functional outcome at 6 months after stroke.
MRI and clinical examinations were performed in 12 patients in the acute phase, at 1 and 6 months after stroke. Twelve age- and gender-matched controls underwent 2 MRIs 1 month apart. Structural remodeling after stroke was assessed using diffusion MRI with an automated measurement of generalized fractional anisotropy (GFA), which was calculated along connections between contralesional cortical motor areas. The predictive model of poststroke functional outcome was computed using a linear regression of acute GFA measures and the clinical assessment.
GFA changes in the contralesional motor tracts were found in all patients and differed significantly from controls (0.001 ≤ p < 0.05). GFA changes in intrahemispheric and interhemispheric motor tracts correlated with age (p ≤ 0.01); those in intrahemispheric motor tracts correlated strongly with clinical scores and stroke sizes (p ≤ 0.001). GFA measured in the acute phase together with a routine motor score and age were a strong predictor of motor outcome at 6 months (r(2) = 0.96, p = 0.0002).
These findings represent a proof of principle that contralesional diffusion MRI measures may provide reliable information for personalized rehabilitation planning after ischemic motor stroke.
[Show abstract][Hide abstract] ABSTRACT: The role of the non-injured hemisphere in stroke recovery is poorly understood. In this pilot study, we sought to explore the presence of structural changes detectable by diffusion tensor imaging (DTI) in the contralesional hemispheres of patients who recovered well from ischemic stroke.
We analyzed serial DTI data from 16 stroke patients who had moderate initial neurological deficits (NIHSS scores 3-12) and good functional outcome at 3-6 months (NIHSS score 0 or modified Rankin Score ≤1). We segmented the brain tissue in gray and white matter (GM and WM) and measured the apparent diffusion coefficient (ADC) and fractional anisotropy in the infarct, in the contralesional infarct mirror region as well as in concentrically expanding regions around them.
We found that GM and WM ADC significantly increased in the infarct region (p < 0.01) from acute to chronic time points, whereas in the infarct mirror region, GM and WM ADC increased (p < 0.01) and WM fractional anisotropy decreased (p < 0.05). No significant changes were detected in other regions.
DTI-based metrics are sensitive to regional structural changes in the contralesional hemisphere during stroke recovery. Prospective studies in larger cohorts with varying levels of recovery are needed to confirm our findings.
European Neurology 05/2012; 67(6):370-6. DOI:10.1159/000336062 · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In acute ischemic stroke the early and accurate prediction of tissue outcome is important to decisions regarding therapy. One proposed prediction approach is to combine structural, perfusion, and diffusion MRI in a generalized linear model (GLM) to predict voxel outcome. Such a model, however, does not account for the spatial correlation likely to be present in voxels that result in infarction. A simple spatial correlation model extension of GLM is presented in this paper; showing moderate improvement in the prediction accuracy.
[Show abstract][Hide abstract] ABSTRACT: Voxel-based algorithms using acute multiparametric-MRI data have been shown to accurately predict tissue outcome after stroke. We explored the potential of MRI-based predictive algorithms to objectively assess the effects of normobaric oxygen therapy (NBO), an investigational stroke treatment, using data from a pilot study of NBO in acute stroke.
The pilot study of NBO enrolled 11 patients randomized to NBO administered for 8 hours, and 8 Control patients who received room-air. Serial MRIs were obtained at admission, during gas therapy, post-therapy, and pre-discharge. Diffusion/perfusion MRI data acquired at admission (pre-therapy) was used in generalized linear models to predict the risk of lesion growth at subsequent time points for both treatment scenarios: NBO or Control.
Lesion volume sizes 'during NBO therapy' predicted by Control-models were significantly larger (P = 0.007) than those predicted by NBO models, suggesting that ischemic lesion growth is attenuated during NBO treatment. No significant difference was found between the predicted lesion volumes at later time-points. NBO-treated patients, despite showing larger lesion volumes on Control-models than NBO-models, tended to have reduced lesion growth.
This study shows that NBO has therapeutic potential in acute ischemic stroke, and demonstrates the feasibility of using MRI-based algorithms to evaluate novel treatments in early-phase clinical trials.