For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO2. The focus of this research has been to validate the hypothesis that has been assumed, but not proven over the past century, that radiation treatment focused specifically on hypoxic regions of tumors would improve tumor curability. This research used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO2 images in volume elements or voxels of murine tumors with 1 torr pO2 resolution and 0.7 mm spatial resolution in FSa fibrosarcomas in the legs of C3H mice. We define hypoxic regions of tumors as those whose image subvolumes or voxels have low pO2, voxels less than 10 torr. We have established EPR pO2 imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO2 based dose painting improves tumor cure, we implemented the XRAD225Cx system to deliver gantry based x-ray treatments to mouse tumors accurately registered with EPR pO2 images. All tumors were pretreated with a dose of radiation that had been determined in separate experiments to cure 30% of tumors, a TCD30. Conclusive failure to demonstrate a difference between treating crude spherical volumes including ~ 85% of hypoxic voxels with an additional curative dose compared with treatment with shells of radiation avoiding hypoxia (anti-boosts) proved tenets of radiation biology: a few surviving hypoxic clonogens cause radiation treatment failure. In response, we implemented rapid 3D printing Tungsten loaded, highly conformal plastic blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance, treating similar volumes of well oxygenated tumor. Only then did we observe significant (p<0.01) tumor control differences between hypoxic boosts and anti-boosts. This is the first validation of the curative effectiveness of focusing hypoxia based dose painting in mammalian tumors.

Citation Format: Howard J. Halpern, Boris Epe;, Matthew C. Maggio, Martyna Krzykawska-Serda, Gage H. Redler, Richard C. Miller, Eugene D. Barth, Ralph R. Weichselbaum. First demonstration that hypoxia targeting with radiation improves tumor control in a mammal tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1874. doi:10.1158/1538-7445.AM2017-1874