TU‐E‐214‐04: NMR Assessment of Tumor Hypoxia and Oxygen Dynamics

Hypoxia is recognized to influence solid tumor response to therapy and has been related to tumor aggressiveness, including growth, development, and metastatic potential [1]. In the context of this symposium, principles and methods based on nuclear magnetic resonance will be discussed, considering practicalities and limitations for applications ranging from the laboratory to the clinic [2]. “F MRI oximetry based on perfluorocarbon reporter molecules not only indicates hypoxia in vivo, but significantly reveals spatial distribution of pO₂ quantitatively, with a precision relevant to radiation biology [3]. Successive measurements may be repeated non‐invasively to reveal hypoxiation during tumor growth or as an acute response to interventions (e.g., breathing hyperoxic gas or administering vascular disrupting agents). Analogous proton MRI methods are also feasible [4], but each requires an exogenous reporter molecule, currently limiting investigations to pre‐clinical studies. In patients, oxygen sensitive proton MRI of tissue water is particularly promising. BOLD (blood oxygen level dependant) contrast MRI is sensitive to the concentration of vascular deoxyhemoglobin, which is paramagnetic causing accelerated R₂* and signal loss in T₂*‐weighted images. However, signal may additionally be perturbed by vascular volume, flow and hematocrit [5]. Meanwhile, TOLD (tissue oxygen level dependant) contrast MRI is directly responsive to pO₂, since the oxygen molecule in paramagnetic influencing the T₁ [6]. The TOLD response is typically smaller than BOLD, but we believe that together they validate interpretation of oxygen sensitivity. We believe that DOCENT (Dynamic Oxygen Challenge Evaluated by NMR T₁ and T₂*) offers a potential test to identify tumor hypoxia and responsiveness to interventions. The ability to stratify patients according to the oxygen characteristics of a tumor becomes increasingly relevant with the development of high dose stereotactic body radiation therapy (SBRT). We believe we are at a historic juncture, where we not only have technologies for identifying hypoxia, but more importantly methods of tailoring therapy successfully to accommodate or exploit the killing of hypoxic cells. 1. Tatum, J.L., et al., Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int. J. Radiat. Biol., 2006. 82(10): p. 699 – 757. 2. Mason, R.P., et al., Multimodality imaging of hypoxia in preclinical settings. QJ Nucl. Med. Mol. Imaging, 2010. 54: p. 259–80. 3. Zhao, D., L. Jiang, and R.P. Mason, Measuring Changes in Tumor Oxygenation. Methods Enzymol, 2004. 386: p. 378–418. 4. Kodibagkar, V.D., et al., Proton Imaging of Siloxanes to map Tissue Oxygenation Levels (PISTOL): a tool for quantitative tissue oximetry. NMR Biomed 2008. 21: p. 899–907. 5. Howe, F.A., et al., Issues inflow and oxygenation dependent contrast (FLOOD) imaging of tumours. Nmr in Biomedicine, 2001. 14(7–8): p. 497–506. 6. Matsumoto, K., et al., MR assessment of changes of tumor in response to hyperbaric oxygen treatment. Magn. Reson. Med., 2006. 56(2): p. 240–246. Learning Objectives: 1. Understand the principles of quantitative MRI oximetry. 2. Understand the possibilities of oxygen sensitive MRI (BOLD and TOLD). 3. Understand the criteria for clinical relevance.