Living tissue hypoxic resistance to radiation, has been known for over a century. Our research has validated the hypothesis that radiation dose boosts focused specifically on hypoxic regions of tumors would improve tumor curability in a fibrosarcoma mouse model. We used Electron Paramagnetic Resonance (EPR) imaging of absolute pO2 in volume elements of murine tumors with 1 torr pO2 resolution and 0.7 mm spatial resolution in FSa fibrosarcomas in the legs of C3H mice. Hypoxia was defined as subvolumes or voxels with pO2 less than 10 torr. This showed EPR pO2 images as a reliable identifier and locator of relevant radiobiologically hypoxia. For the first time in mammalian tumors pO2 based dose painting was shown to improves tumor cure. This required gantry based x-ray treatment with an XRAD225Cx system to deliver dose to mouse tumors accurately registered with EPR pO2 images. Tumors were pretreated with a dose of radiation sufficient to cure 15% of tumors, a TCD15. For hypoxic boosts or hypoxia avoidance of the same volume, 3D printing Tungsten loaded, highly conformal plastic blocks were used. This allowed comparison of treating 100% of hypoxic tumor voxels with hypoxia avoidance boosts. This showed significant (p=0.02) tumor control differences between hypoxic boosts and hypoxia avoiding boosts. This is the first validation of the curative effectiveness of focusing hypoxia based dose painting in mammalian tumors. This was motivated by a conclusive failure to demonstrate a difference between treating ~ 85% of hypoxic voxels with a hypoxic boost compared with radiation avoiding hypoxia which proved tenets of radiation biology: a few surviving hypoxic clonogens cause radiation treatment failure.

To further validate this approach, we have applied the same techniques to a second mouse mammary carcinoma, the MCa4. We have determined the dose response of 325 μl IM tumors in C3H mouse legs with a 50% control at 180 days with 52 Gy radiation (the TCD50). We have begun the study of tumor control using a whole tumor TCD15 of 49 Gy and boosts of 11 Gy to hypoxic and well oxygenated tumor of the same volume. With a median follow up of35 days of 10 animals, none of the hypoxic boost cohort have failed. All failure has been in the well oxygenated tumor boost cohort. Log-Rank significance is ~0.2. Our past experience has been that these early results portend future significance.

Support: R01 CA098575, P41 EB002035, R50 CA211408

Citation Format: Howard J. Halpern, Boris Epel, Matthew C. Maggio, Martyna Krzykawska-Serda, Gage H. Redler, Richard C. Miller, Eugene D. Barth, Ralph R. Weichselbaum, Victor M. Tormyshev. Second tumor type showing hypoxia targeting with radiation improves tumor control in a mammal tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4157.