Tumor growth and vascular redistribution contributes to the dosimetric preferential effect of microbeam radiotherapy: a Monte Carlo study

Abstract

The radiobiological mechanisms behind the favorable response of tissues to microbeam radiation therapy (MRT) are not fully described yet. Among other factors, the differential action to tumor and normal tissue vasculature is considered to contribute to MRT efficacy. This computational study evaluates the relevance of tumor growth stage and associated vascular redistribution to this effect. A multiscale approach was employed with two simulation softwares: TOPAS and CompuCell3D. Segmentation images of the angioarchitecture of a non-bearing tumor mouse brain were used. The tumor vasculature at different tumor growth stages was obtained by simulating the tumor proliferation and spatial vascular redistribution. The radiation-induced damage to vascular cells and consequent change in oxygen perfusion were simulated for normal and tumor tissues. The multiscale model showed that oxygen perfusion to tissues and vessels decreased as a function of the tumor proliferation stage, and with the decrease in uniformity of the vasculature spatial distribution in the tumor tissue. This led to an increase in the fraction of hypoxic (up to 60%) and necrotic (10%) tumor cells at advanced tumor stages, whereas normal tissues remained normoxic. These results showed that tumor stage and spatial vascular distribution contribute to the preferential effect of MRT in tumors.

Keywords: Computational modeling; Microbeam radiotherapy; Spatially fractionated radiotherapy; Vasculature.

Figure 1

Temporal evolution of vascular pO₂ after vascular cell death. (a) Representation of cell configuration after death (MCS = 100). (b) Temporal evolution of vascular pO₂ in the different cells shown in (a). The dotted vertical line shows the moment cells #10 and #30 are removed from the capillary (time = 100 MCS).

Figure 2

(a) MRT dose profile at the center of the scoring volume, and (b) probability of vascular cell death as a function of the absorbed dose. Experimental data from.

Figure 3

3D visualization of the normal tissue and tumor (D12, D16, and D20) geometries. For the sake of visualization, the normal tissue cells are not shown.

Figure 4

Visualization (2D slice at the center of the lattice) of the spatial distribution of intact and dead cells after MRT irradiation in normal tissue and tumor (D12, D16, and D20) scenarios. Black arrows indicate the direction of microbeams.

Figure 5

(a) Cellular levels of pO₂ pre- and post MRT irradiation in normal tissue and tumor (D12, D14, D16, D18, and D20) scenarios. Solid lines indicate mean values, and the shadow areas correspond to one standard deviation. The vertical grey line indicates the time of the MRT irradiation (t = 30 min). (b) Fraction of unperfused vascular cells at the steady state after MRT in normal tissue and tumor scenarios. (c) Relationship between pO₂ depletion after MRT irradiation (with respect to pre-irradiation) and the decrease in spatial uniformity of vasculature (expressed with respect to the normal tissue vasculature uniformity).

Figure 6

Fraction of normoxic, hypoxic, necrotic and total dead cells pre and post MRT irradiation in normal tissue and tumor (D16, D18, and D20) scenarios. The fraction of total dead cells is the sum of necrotic cells due to the low levels of pO₂ and cell dead by the direct action of radiation. The vertical solid grey line indicates the time of the MRT irradiation (t = 30 min).