Abstract
Hypoxia is frequently found in solid tumors and is known to increase the resistance to several kinds of treatment modalities including radiation therapy. Besides, the treatment response is also largely determined by the total number of clonogenic cells, i.e., cells with unlimited proliferative capacity. Depending on the duration of hypoxia, the rate of proliferation and hence also the clonogen density could be expected to differ in hypoxic compartments. The combination at the microscale between heterogeneous tumor oxygenation and clonogen density could therefore be crucial with respect to the outcome of a radiotherapy treatment. In this study it was investigated the impact of heterogeneous clonogen density on the outcome of stereotactic radiotherapy treatments of hypoxic tumors. A recently developed three-dimensional model for tissue vasculature and oxygenation was used to create realistic in silico tumors with heterogeneous oxygenation. Stereotactic radiotherapy treatments were simulated, and cell survival was calculated on a voxel-level accounting for the oxygenation. For a tumor with a diameter of 1 cm and a baseline clonogenic density of 107/cm3 for the normoxic subvolume, when the relative density for the hypoxic cells drops by a factor of 10 the tumor control probability (TCP) decreases by about 10% when relatively small hypoxic volumes and few fractions are considered; longer treatments tend to level out the results. With increasing size of the hypoxic subvolume, the TCP decreased overall as expected, and the difference in TCP between a homogeneous and a heterogeneous distribution of cells increased. The results demonstrate a delicate interplay between the heterogeneous distribution of tumor oxygenation and clonogenic cells that could significantly impact on the treatment outcome of radiotherapy.
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Acknowledgments
Financial support from the Cancer Research Funds of Radiumhemmet and The Swedish Research Council (2020-04618) is gratefully acknowledged. The computations were partly enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at “PDC Center for High Performance Computing, KTH Royal Institute of Technology” partially funded by the Swedish Research Council through grant agreement no. 2018-05973.
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Schiavo, F., Toma-Dasu, I., Kjellsson Lindblom, E. (2023). The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy. In: Scholkmann, F., LaManna, J., Wolf, U. (eds) Oxygen Transport to Tissue XLIV. ISOTT 2022. Advances in Experimental Medicine and Biology, vol 1438. Springer, Cham. https://doi.org/10.1007/978-3-031-42003-0_20
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DOI: https://doi.org/10.1007/978-3-031-42003-0_20
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