High-, moderate- and low-LET ion beams for treatment of radioresistant tumors: Impact of beam quality, tumor grading and hypoxic status on radiation response

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Ion beam radiotherapy has emerged as a promising modality to treat radioresistant tumors with unsatisfying cure rates after photon therapy. The depth dose profile (Bragg-Peak) of ions allows for increasing the dose to the tumor dose while still respecting the tolerance of the adjacent normal tissue. Besides this, ion beams exhibit an increased relative biological effectiveness (RBE) compared to photons, which depends on the ion type and rises with linear energy transfer (LET). The LET of ions may be classified as low (protons), moderate (4He-ions) or high (12C- or 16O-ions). Besides protons, a few centers provide 4He-, 12C- or 16O-ions as additional strategy to fight cancer. Compared to protons, 4He-ions offer an increased physical selectivity with only a moderately increased RBE. 12C- and 16O-ions are considered attractive, especially for the treatment of hypoxic tumors as high-LET radiation is expected to reduce the oxygen enhancement ratio (OER). A decision on which ion type is suited best for which tumor is currently prevented by the lack of clinical and biological data. Especially for 4He-ions as a moderate-LET modality, the potential of treating different tumor types is only poorly understood.As continuation of our previous project (DFG, GL 893/1-1, KA 2679/3-1), we propose a preclinical study to quantify the impact of intrinsic hypoxia (given by the grading of the tumor) as well as the role of acute hypoxia (induced by clamping of the tumor-supplying artery) on the tumor response after irradiation with clinically envisaged ion beams. The project includes dose-response studies for three different tumor-sublines of a rat prostate tumor model after irradiation with proton, 4He-, 12C- or 16O-ion beams. Determining the doses at 50% local tumor control probability (TCD50) at 300 days, the RBE (photon vs. ion beams) and OER (clamping vs. non-clamping condition) values will be calculated for each ion species and tumor type. To characterize the hypoxic status and perfusion of the tumors prior and after irradiation, 18F-MISO PET, photoacoustic imaging and T1-weighted DCE-MRI measurements will be performed and evaluated quantitatively. Imaging studies will be supplemented by histological investigations of the vascular architecture (CD31, SMA), hypoxia (pimonidazole, CCI103F, CAIX), perfusion (Hoechst 33342), proliferation (BrdU) and on the radiation induced immune response (macrophages, CD4+ and CD8+ T-cells as well as NK-cells).This project will deliver comprehensive biological data urgently needed to validate and improve the RBE-models used in patients. Extending the range of ions beyond protons and 12C-ions could open new treatment strategies by optimizing the dose conformation to tumors, minimizing the impact of tumor heterogeneity and radiation resistance and thereby to increase the clinical outcome with a minimum of side effects.