Early effects in epithelial tissues: The role of stem cells and time factors

During radiotherapy for cancers, normal tissues can be unavoidably co-irradiated, potentially resulting in side effects that can be tumor dose-limiting and/or affect the patient's quality of life. In general, radiotherapy side effects are separated into early (acute) and late (chronic) effects with an arbitrary cut-off of 90 days. Most importantly, the mechanisms involved in the early versus late response differ to a large extent. Early side effects occur mainly in tissue with a high proliferative activity. The symptoms are due to the progressive loss of cells and are accompanied by an acute inflammatory response often imperative to the regenerative response. Recovery is often complete due to the high proliferative state of the surviving stem/progenitor cells and/or migration of stem/progenitor cells from outside the radiation field. Early reactions can significantly impact a patient's general status and health-related quality of life and thus can result in unintended treatment interruptions. Some early responses are dose-limiting, such as oral mucositis in radiotherapy of advanced head-and-neck tumors, and hence reducing the chance of tumor cure. In addition, the costs of supportive care are an important socio-economic factor. As these effects are usually observed over several days to weeks, they should be termed early rather than acute, as the latter in medicine generally refers to a time course of hours to a few days. Additional traumata can significantly aggravate early radiation responses, e.g. resulting from chemotherapy as one prominent example. Moreover, mechanical stress can influence early complications in epithelial tissues, such as epidermal irritation by clothing or in skin folds or oral mucosal trauma through dental prostheses or sharp-edged food components. Similarly, chemical exposure can intensify the response, like smoking, alcohol or spicy diet in oral mucosa, as well as additional physical factors, such as exposure of irradiated epidermis to ultraviolet irradiation. Such exacerbating factors should hence be avoided during radiotherapy.