Voxel-based analysis in radiation oncology: A methodological cookbook.

Recently, 2D or 3D methods for dose distribution analysis have been proposed as evolutions of the Dose Volume Histogram (DVH) approaches. Those methods, collectively referred to as pixel- or voxel-based (VB) methods, evaluate local dose response patterns and go beyond the organ-based philosophy of Normal Tissue Complication Probability (NTCP) modelling. VB methods have been introduced in the context of radiation oncology in the very last years following the virtuous example of neuroimaging experience. In radiation oncology setting, dose mapping is a suitable scheme to compare spatial patterns of local dose distributions between patients who develop toxicity and who do not. In this critical review, we present the methods that include spatial dose distribution information for evaluating different toxicity endpoints after radiation therapy. The review addresses two main topics. First, the critical aspects in dose map building, namely the spatial normalization of the dose distributions from different patients. Then, the issues related to the actual dose map comparison, i.e. the viable options for a robust VB statistical analysis and the potential pitfalls related to the adopted solutions. To elucidate the different theoretical and technical issues, the covered topics are illustrated in relation to practical applications found in the existing literature. We conclude the overview on the VB philosophy in radiation oncology by introducing new phenomenological approaches to NTCP modelling that accounts for inhomogeneous organ radiosensitivity.