Noninvasive Assessment of Tumor Hypoxia Using MRI in Clinical and Preclinical Tumor Models

Abstract

Tumor oxygenation influences response to radiation and plays important roles in malignant progression, angiogenesis and metastasis. While methods are available to quantitatively map pO2 dynamics in preclinical studies, new techniques are needed to noninvasively characterize tumor hypoxia and response to interventions in patients. Blood Oxygen Level Dependent (BOLD) MRI based on T2* contrast induced by deoxyhemoglobin concentration [dHb] is sensitive to tumor vascular oxygenation and blood flow. Meanwhile TOLD (Tissue Oxygen Level Dependent) MRI is sensitive to tissue oxygenation based on the shortening of the tissue water T1 due to molecular oxygen [O2]. In this study, I investigate the utility of BOLD and TOLD to evaluate tumor hypoxia in response to breathing hyperoxic gas in rats and test the feasibility of such measurements in patients. All MRI experiments were performed on either a 4.7T small animal Varian or a 3T clinical Philips scanner. Variation in BOLD and TOLD signal response observed in two syngeneic prostate tumor models: Dunning R3327-AT1 and -HI, with respect to oxygen and carbogen breathing were compared with quantitative change in pO2 measured using Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping (FREDOM). In addition, BOLD and TOLD MRI measurements were used to predict radiation treatment outcome following a single dose of 30 Gy. BOLD MRI was also assessed in cervical cancer patients in response to breathing oxygen (15dm3/min). Two sequences were tested, multiple-shot EPI and multi echo gradient echo, to allow comparison. Significant correlations were found between BOLD and TOLD MRI and quantitative pO2 measurements for both oxygen and carbogen breathing. However, both gases had similar effect on modulating tumor hypoxia with no significant difference observed. The AT1 tumors showed a correlation between tumor growth delay for the animals breathing O2 during radiation and pre-irradiation TOLD responses to oxygen challenge. Finally, BOLD MRI at 3T was feasible for examining the potentially valuable biomarker of oxygenation seen in cervical cancer. Further parameters such as vascular perfusion and permeability based on DCE, cellularity based on diffusion, and TOLD response to oxygen challenge may also be readily incorporated into a dynamic evaluation.