Normal tissue tolerance

Effects of radiation exposure are observed in virtually all normal tissues. Early reactions occur primarily in turnover tissues (e.g., bone marrow, epidermis, mucosae of the gastrointestinal tract), where proliferative impairment results in progressive hypoplasia and eventually complete loss of functional cells, after a tissue dependent but dose independent latent time. These early radiation reponses are regularly preceded and accompanied by vascular and inflammatory reactions. In contrast, late reactions are based on combined parenchymal, vascular, and connective tissue changes; very late effects are dominated by vascular sequelae. In most instances, a significant involvement of the immune system can also be demonstrated for chronic radiation sequelae, and a contribution of neural changes is discussed. The orchestrated response of all tissue components results in loss of function within the exposed volume. Importantly, latent times of late effects are inversely dependent on dose. Hence modern, highly conformal treatment techniques with relatively low and inhomogeneous doses in the organs at risk (OAR) require very long follow-up intervals with a precise assessment and documentation of the complication endpoints for characterisation of the treatment-induced morbidity profile. Consequential late effects (CLEs) develop through interactions between early and late effects in the same organ; they follow the radiobiological principles of the early reactions. The clinical manifestation of radiation responses is defined by several parameters, summarized as the “R’s of radiobiology”. First, each individual symptom or endpoint of radiation-induced morbidity follows an individual dose-effect relationship (intrinsic ‘R’adiosensitivity), in many instances related to the dose within specific subvolumes of the individual OAR, rather than e.g., the mean organ dose. The biological effectiveness of a certain (total) dose is modulated by exposure conditions: Changes in dose fractionation protocols (‘R’recovery) predominantly impact on late responding tissues, while overall treatment time (‘R’epopulation) predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure (i’R’adiated volume”) are related to tissue architecture. In mainly ‘tubular’ or ‘serial’ organs (e.g., gastrointestinal tract, but also vasculature), local exposure affects function in downstream compartments. In contrast, in predominantly ‘parallel’ organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. However, all organs in fact are composed of tubular and serial components. Translational studies into damage processing (molecular ‘R’adiopathology), starting immediately after the onset of radiation exposure, but proceeding for long and very long time intervals even at subclinical levels, intra- and intercellular signals and signalling pathways may be identified that are relevant or even specific for the clinical manifestation of morbidity endpoints. These can serve as a basis to identify (early) biomarkers of the individual risk for specific tissue reactions and endpoints, and also for establishment of strategies to prevent/mitigate tissue effects after exposure.