The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited. This paper examines the radiobiological mechanisms underlying the most important complications induced by radiotherapy, with the aim of identifying the essential parameters and functional relationships needed for effective predictive NTCP models. The clinical features of the complications are identified and reduced as much as possible into component parts. In a second step, experimental and clinical data are considered in order to identify the gross anatomical structures involved, and which dose distributions lead to these complications. Finally, the pathogenic pathways and cellular and more specific anatomical parameters that have to be considered in this pathway are determined. This analysis is carried out for some of the most critical organs and sites in radiotherapy, i.e. spinal cord, lung, rectum, oropharynx and heart. Signs and symptoms of severe late normal tissue complications present a very variable picture in the different organs at risk. Only in rare instances is the entire organ the critical target which elicits the particular complication. Moreover, the biological mechanisms that are involved in the pathogenesis differ between the different complications, even in the same organ. Different mechanisms are likely to be related to different shapes of dose effect relationships and different relationships between dose per fraction, dose rate, and overall treatment time and effects. There is good reason to conclude that each type of late complication after radiotherapy depends on its own specific mechanism which is triggered by the radiation exposure of particular structures or sub-volumes of (or related to) the respective organ at risk. Hence each complication will need the development of an NTCP model designed to accommodate this structure.
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