EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

Abstract

Clinical trials to ameliorate hypoxia as a strategy to relieve the radiation resistance it causes have prompted a need to assay the precise extent and location of hypoxia in tumors. Electron Paramagnetic Resonance oxygen imaging (EPR O2 imaging) provides a non-invasive means to address this need. To obtain a preclinical proof of principle that EPR O2 images could predict radiation control, we treated mouse tumors at or near doses required to achieve 50 percent control (TCD50). Mice with FSa fibrosarcoma or MCa4 carcinoma were subjected to EPR O2 imaging and immediately radiated to a TCD50 or TCD50 ±10 Gy.. Statistical analysis was permitted by collection of ~ 1300 tumor pO2 image voxels, including the fraction of tumor voxels with pO2 less than 10 mm Hg (HF10). Tumors were followed for 90 days (FSa) or 120 days (MCa4) to determine local control or failure. HF10 obtained from EPR images showed statistically significant differences between tumors that were controlled by the TCD50 and those that were not controlled for both FSa and MCa4. Kaplan-Meier analysis of both types of tumors showed ~90% of mildly hypoxic tumors were controlled (HF10<10%), and only 37% (FSA) and 23% (MCa4) tumors controlled if hypoxic. EPR pO2 image voxel distributions in these ~0.5 ml tumors provide a prediction of radiation curability independent of radiation dose. These data confirm the significance of EPR pO2 hypoxic fractions. The ~90% control of low HF10 tumors argue that ½ ml subvolumes of tumors may be more sensitive to radiation and may need less radiation for high tumor control rates.

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

“…Based on survival data, HP 10 was most strongly correlated with curative treatment (pseudo-R 2 = 0.59) and identifying tumors at risk for treatment failure, consistent with clinical data obtained from oxygen-sensitive electrodes. In a follow-up radiation treatment study, HP 10 > 10% and HP 10 > 15% were predictive for treatment failure in FSa tumors and MCa4 (mammary carcinoma) tumors, respectively (81). The hypoxic treatment outcomes cut-offs observed in this study are similar to hypoxic cut-offs observed in human patients.…”

The evolution of biomedical EPR (ESR)

“…of Brussels, have embarked on studies to localize areas for eventual surgical removal or correction of regions that have reduced oxygen tension due to tumors, or as a calibration of oxygen pressures suitable for subsequent radiation therapy that has also been a major thrust in the Univ. of Chicago group as well, who are experts on radiation treatment of tumors and tissue [28,29,42].…”

Approaching Oxygen-Guided Intensity-Modulated Radiation Therapy

“…It is known that tumors treated to a uniform 50% tumor control dose (TCD 50 ) exhibit different control probability depending on their oxygenation (Fig. 1) [2]. Hypoxia desensitizes tumors to radiation and mandate higher treatment doses.…”