Abstract IA11: Perfusion MRI: A potential biomarker of tumor response in clinical trials
Authors: Emblem Kyrre E. 
Published: December 2015

Abstract
This presentation will show an overview of perfusion MRI for in vivo imaging of solid cancers and emerging evidence supporting the use of this technique to monitor response to anticancer therapy is discussed.
The noninvasive nature and high image resolution of Magnetic Resonance Imaging (MRI) makes it the preferred modality for in vivo imaging and disease monitoring of most solid cancers. While conventional MRI provides important anatomic information on the tumor and surrounding tissue, it reveals fewer insights on the metabolic and hemodynamic status and function of the tumor. With the advent of antiangiogenic agents that are not directly cytotoxic, there is an urgent need for clinical trials to incorporate advanced imaging analyses that goes beyond traditional and formalized imaging-based response criteria – usually by assessing tumor load after contrast agent administration. Blockade of vascular endothelial growth factors (VEGF) results in decreased vascular permeability and reduced tumor contrast enhancement on conventional MRI, artificially boosting radiographic response rates. Unfortunately, the high response rates do not always translate into prolonged survival [1]. The negative results of several recent late-phase trials suggest that first-line administration of antiangiogenic therapies in unselected patient groups is probably not the best approach, owing to diversity in cancer biology and natural history. Identification of a subset of cancer patients most likely to benefit from therapy and understanding the underlying mechanisms that separate these responding patients from non-responders are of high priority. According to the National Cancer Institute imaging response criteria [2], developing and validating clinical trial-acceptable advanced imaging methods can lead to smaller clinical trials with fewer patients by earlier and more-focused response assessments; faster regulatory approvals, and by this, earlier use of new drugs in clinical care.
Dynamic contrast-enhanced MRI, or perfusion MRI, may help address the limitations of conventional imaging methods in antiangiogenic trials and complement these imaging exams with information on vascular permeability, blood flow and blood volume, among others. A large number of retrospective human studies show consistent reductions in abnormal vascular permeability after antiangiogenic therapy in a range of cancer types [3]. Small studies of brain tumor patients treated with VEGFR inhibitors also show a transient normalization of inefficient blood flow in a selected group of patients and suggest that vascular normalization may be a mechanism for improved delivery of adjuvant therapy and prolonged survival [4]. Similar data on changes in relative blood volume also show a sensitive, yet more complex response to VEGFR inhibition [5]. These efforts are followed by the recent introduction of MRI-based measurements of tumor vessel caliber and relative tissue oxygen saturation in clinical trial data [6]. These measurements are made possible using MR images sensitive to the vessel-size-related scale of magnetic field inhomogeneities created by blood and contrast agents flowing through the vessels. Most, if not all major manufacturers of MRI apparatus now provide these dedicated image protocols. Collectively, perfusion MRI may provide the clinical decision maker with a battery of complementary parameters capable of identifying the initial response, duration and end of the vascular remodeling period following antiangiogenic therapy and thereby enable early identification of patients most likely to benefit from targeted therapies.
References:
[1] Ellingson BM et al, Neuro Oncol 2011; doi:10.1093/neuonc/noq206.
[2] http://imaging.cancer.gov/clinicaltrials/imaging
[3] O'Connor JP et al, Nat Rev Clin Oncol 2012; doi:10.1038/nrclinonc.2012.2.
[4] Batchelor TT et al, PNAS 2013; doi:10.1073/pnas.1318022110.
[5] Schmainda KM et al, Neuro Oncol 2014; doi: 10.1093/neuonc/not216.
[6] Emblem KE et al, Nat Rev Clin Oncol 2014; doi: 10.1038/nrclinonc.2014.
Citation Format: Kyrre E. Emblem. Perfusion MRI: A potential biomarker of tumor response in clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA11.