Consequential late effects in normal tissues

Unconventional, more aggressive irradiation protocols are usually associated with aggravation of acute reactions. In recent clinical studies, this has resulted in modulation of late effects in the same organ. This phenomenon has been termed consequential late effect (CLE). Correlations between acute and late effects have been reported in a number of tissues. Moreover, some radiobiological parameters may be used to differentiate between consequential and generic late effects: Dose fractionation and overall treatment time have a similar effect on acute and consequential responses, but opposing effects on generic late effects. Modulation of acute effects will affect the consequential component of late sequelae. Similarly, it will be influenced by the irradiated volume if a volume effect exists for the acute response. Moreover, markers for the acute response should be predictive for consequential effects. The present review gives preclinical and clinical evidence for CLE. These are predominantly found in organ systems where the acute response (of the epithelial lining) is associated with an impairment of the barrier against mechanical or chemical stress, which may cause additional trauma to the underlying tissues. Therefore, CLE are mainly found in the urinary and intestinal system, in mucosa and, to some extent, in skin. In these tissues with a consequential component of the late sequelae, amelioration of the acute response to irradiation may be a useful approach to minimize late side effects of effective radiation therapy.