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Purpose: Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify nonresponding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the parametric response map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction. Experimental Design: Forty-five high-grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pretreatment and 3 weeks midtreatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated. Results: Multivariate analysis showed that PRMADC+ in combination with PRMrCBV− obtained at week 3 had a stronger correlation to 1-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, nonresponders [median survival (MS) of 5.5 months, 95% CI: 4.4–6.6 months], partial responders (MS of 16 months, 95% CI: 8.6–23.4 months), and responders (MS has not yet been reached). Conclusions: Inclusion of PRMADC+ and PRMrCBV− into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (Macdonald criteria), the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies. Clin Cancer Res; 17(14); 4751–60. ©2011 AACR.

Purpose: To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT). Experimental Design: Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed. Results: No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P < 0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P < 0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P < 0.02) and frontal lobes (P < 0.03), and changes in BBB permeability of left frontal lobes during RT (P < 0.007). A similar correlation was found between recall scores and BBB permeability. Conclusion: Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.

The purpose of this study was to evaluate the diagnostic performance of MRI based T1 and relative cerebral blood volume (rCBV) maps analyzed a multi-modality voxel-based analysis referred to as multi-parametric response mapping (mPRM) for early chemoradiation response prediction in patients diagnosed with high-grade gliomas. Patients (n=23) with Grade III/IV glioma were recruited in a prospective imaging trial. Patients underwent MRI before RT, 1 and 3 weeks after RT. The MRI protocol included fluid-attenuated inversion recovery imaging (FLAIR), quantitative T1 mapping, dynamic contrast-susceptibility T2*-weighted imaging (rCBV) and contrast-enhanced T1-weighted imaging (CE-T1w). All images were co-registered to CE-T1w images acquired before RT. Following co-registration, the tumor VOIs were manually contoured either on the CE-T1w or on the FLAIR images and applied to the rCBV and T1maps. For each patient, mid-treatment time point and VOI the percentage change, PRM and mPRM techniques were used to analyze data. Briefly, PRM was performed by calculating the difference in the rCBV values of each voxel within the tumor at mid-treatment values with respective pre-treatment values. A threshold was then applied to the absolute difference of the rCBV in a voxel and all like voxels were summed to obtain tumor volume fractions that showed significantly increasing (PRMrCBV+), decreasing (PRMrCBV-), and unchanged (PRMrCBV0) rCBV values following therapy. We used the same procedure for determining the PRM of T1 maps. mPRMs maps were computed by combining both PRMs (T1 and rCBV) in a single color map. Receiver operator characteristic analysis (ROC), assessed for 12 month survival, was used to determine the optimal cutoff for each parameter. The patient population was then stratified based on the optimal cutoffs obtained from the ROC analysis. Overall survival for each parameter was determined using Kaplan-Meier curves and the log-rank test. Standard PRM, using T1or rCBV maps (specifically PRMT1+ and PRMrCBV- metrics) and percentage change methods were found to be predictive of survival only for specific time of acquisition and VOI used. It was determined that mPRMT1+/rCBV- significantly identified patients resistant to therapy irrespective of tumor volume delineation on CE-T1w or FLAIR images and the time point mid-treatment used. Our results show that mPRM improves the sensitivity of quantitative T1 and rCBV maps to predict overall patient survival. This study introduces a new approach for analyzing and combining multi-parametric MR images into a single multi-parametric response map. The mPRM metric showed promise as an early and robust imaging biomarker of treatment response in patients diagnosed with high grade gliomas. This novel approach is a very sensitive tool for analysis of multiparametric and/or multimodal data with enhanced sensitivity for early detection of therapy response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4299. doi:1538-7445.AM2012-4299

We assessed whether a new method of quantifying therapeutic-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high grade glioma. Patients from a prospective IRB-approved trial with high grade glioma received concurrent chemoradiation. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired prior and at week 3 mid-treatment. Pseudoprogression was defined as imaging changes 1-3 months after chemoradiation that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional MR parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Median radiation dose was 72 Gy (range: 60-81). Of 27 patients, stable disease/partial response was noted in 13 and apparent progression in 14. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in 6 patients. Based upon PRM analysis, a significant portion of the tumor volume had reduced rCBV (PRMrCBV) at week 3 in patients with progressive disease compared to those with pseudoprogression (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2698.

We assessed whether quantification of therapeutic-associated tumor cellularity and hemodynamic alterations may help in the early assessment of treatment resistance in patients with high grade glioma. Patients with high grade glioma (n=45) received concurrent chemoradiation. Apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired prior to chemoradiation and at week 3 during treatment on a prospective IRB-approved study. Clinical and conventional MR parameters, including average baseline ADC and rCBV and radiological response, were evaluated as prognostic indicators of one-year survival. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Of 45 patients, median survival was found to be 14.9 months with 44% of patients living shorter than one year (median survival of 6.6 months). Baseline ADC was the only single model not found to be predictive of survival at one year, whereas in a multivariate analysis PRMADC+ and PRMrCBV- had a stronger correlation to survival than baseline rCBV. Overall, a composite model of PRMADC+ and PRMrCBV- was found to have the strongest correlation with one-year survival. This study demonstrates the potential of a composite parametric model sensitive to both tumor cellularity and hemodynamic alterations following first line therapy for providing an early assessment of patient resistant to chemoradiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3754.

Introduction: Standard assessment of radiologic response in patients with malignant glioma is traditionally carried out using T1 gadolinium-enhanced MRI at approximately 10 weeks following treatment initiation. Diffusion-weighted MRI of gliomas, analyzed by the functional diffusion map (fDM), may provide an early measure of response during treatment to predict patient survival (OS). Tumor cells restrict the random diffusion of water molecules within a tumor; therefore, diffusion will increase during successful therapy. The fDM imaging biomarker is a voxel-wise method for analysis of DW-MRI data providing for quantification of treatment-associated spatial alterations in tumor diffusion values earlier than radiologic response. Methods: A prospective single-institution trial of early assessment of brain tumor response by MRI was performed early during radiation therapy. Sixty patients with high grade glioma undergoing radiation therapy were enrolled in an IRB-approved study of intra-treatment MRI 1, 3, and 10 weeks after the initiation of treatment. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at one-year. Log Rank and Cox Proportional Hazards models were utilized to assess OS. Results: Measurable changes in diffusion MRI were observed as early as one week into treatment. The volume of tumor with increased diffusion as assessed by fDM 3 weeks after the start of therapy was the strongest predictor of patient survival at one year, with larger fDM predicting longer median survival [52.6 vs. 10.9 months, log-rank, P Conclusions: Compared to conventional neuro-imaging, fDM provided an earlier assessment of equal predictive value during the course of treatment, providing the opportunity to individualize therapy. The combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.