Prospective analysis of parametric MRI biomarkers: Identification of early and distinct glioma response patterns not predicted by standard radiographic assessment

Running title: MRI biomarker for therapy-induced response in gliomas. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Imaging biomarkers capable of providing early cancer treatment response assessment would allow the opportunity to individualize patient care. For this purpose, images can be obtained which detect treatment-associated alterations in tissue properties including cellular viability, vascular function and volume, biochemical, and molecular responses. In this study, multi-parametric quantification of perfusion and diffusion-weighted MRI brain tumor maps was accomplished using a novel voxel-by-voxel analysis approach know as the parametric response map (PRM). The PRM composite imaging biomarker was found to provide early identification of patients resistant to standard chemoradiation. Validation of the PRM imaging biomarker would allow for routine clinical application as an early identifier of patients who may benefit from alternative treatment strategies. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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 non-responding 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 pre-treatment and 3 weeks mid-treatment 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 PRM ADC+ in combination with PRM rCBV-obtained at week 3 had a stronger correlation to one-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, non-responders (median survival (MS) of 5.5 months CI: 4.4-6.6) months, partial responders (MS of 16 months CI: 8.6-23.4) and responders (MS has not yet been reached.) Conclusions: Inclusion of PRM ADC+ and PRM rCBV-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 …