Voxel-wise analysis: A powerful tool to predict radio-induced toxicity and potentially perform personalised planning in radiotherapy.

Dose - volume histograms have been historically used to study the relationship between the planned radiation dose and healthy tissue damage. However, this approach considers neither spatial information nor heterogenous radiosensitivity within organs at risk, depending on the tissue. Recently, voxel-wise analyses have emerged in the literature as powerful tools to fully exploit three-dimensional information from the planned dose distribution. They allow to identify anatomical subregions of one or several organs in which the irradiation dose is associated with a given toxicity. These methods rely on an accurate anatomical alignment, usually obtained by means of a non-rigid registration. Once the different anatomies are spatially normalised, correlations between the three-dimensional dose and a given toxicity can be explored voxel-wise. Parametric or non-parametric statistical tests can be performed on every voxel to identify the voxels in which the dose is significantly different between patients presenting or not toxicity. Several anatomical subregions associated with genitourinary, gastrointestinal, cardiac, pulmonary or haematological toxicity have already been identified in the literature for prostate, head and neck or thorax irradiation. Voxel-wise analysis appears therefore first particularly interesting to increase toxicity prediction capability by identifying specific subregions in the organs at risk whose irradiation is highly predictive of specific toxicity. The second interest is potentially to decrease the radio-induced toxicity by limiting the dose in the predictive subregions, while not decreasing the dose in the target volume. Limitations of the approach have been pointed out.

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