Pathophysiology And Mediators Of Early Effects

Early effects following radiation exposure follow a similar pattern. There is an initial vascular response, followed by cell depletion and possible secondary effects, and finally healing.

Initial Response

The first observed effects following radiotherapy are vascular and inflammatory. The most commonly seen effect is erythema of the skin or mucous membranes. This is due to release of cytokines from irradiated cells, particularly endothelial cells and macrophages. These factors exert a paracrine effect on the area, leading to vascular dilatation and the resulting erythema and sensation of pain. The cytokines are typically pro-inflammatory, such as interleukin-1a (IL1a), tumour necrosis factor 1α (TNF1 α), or cyclo-oxygenase-2 (COX2).
The development of this acute reaction and its relation to cellular depletion which occurs later is unknown. It is likely that there is some interplay but the mechanism/s have not yet been determined.

Cell Depletion

Cell depletion leads to the clinical problems of early effects. It occurs universally in cycling cell populations, such as bone marrow or epithelium, due to imbalance of cell generation and cell death.
The epithelium is regenerated by tissue stem cells (a functional concept), which exist in the germinal centres of the tissue. They divide into two daughter cells, one of which remains a stem cell while the other becomes a transit cell. These transit cells may undergo further divisions (eg. 10 for bone marrow cells) that allow a single stem cell to generate 210 daughter cells per division. The lifespan of the transit and differentiated cells varies between tissue types – from a few days for gut epithelial cells to months in the urothelium. The turnover time of cells is related to the clinically significant early effects seen in normal tissues.
Radiotherapy at clinical doses is lethal to stem cells, mostly ignored by transit cells, and has no early effect on fully differentiated cells. The loss of the progenitor cells leads to very large losses of differentiated cells that is dose dependent. Importantly, the time until early effects are seen is independent of dose, instead relying on the normal tissue turnover time. In general, the turnover time of a normal tissue is less than the time effects take to appear, due to the ongoing divisions of cells in the transit phase.

Tissue Healing

Replenishment of stem cells occurs through migration of stem cells from outside the treated area, or through division of surviving cells within the treatment area. These surviving cells may enter into specialised divisions, where both daughter cells remain as stem cells. When the stem cells have been replenished, the transit cell population begins to re-appear, leading to the development of the normal epithelium (or other population) and restoration of function.
The time until healing takes place is dependent on total dose and fractionation schedule. Higher doses, or more intense fractionation may both lead to prolonged early effects due to increased stem cell depletion.