Late Skin Reactions

Early skin reactions are common with most treatments, due to cytokine release, death of stem cells in the basal layer of epidermis. These changes usually heal within 1-2 months.
Late effects show a latency of several months to several years. They include telangiectasia, oedema, fibrosis and chronic ulceration.
Skin functional sub-units are conceptually thought of as small areas of epidermis together with the underlying papillary dermis, all supplied by a single small vessel (capillaries). This FSU is about 30 micrometers in diameter and 350 micrometers in depth from the surface of the skin. If one FSU is lost due to radiation, there is the possibility that recovery will occur from surrounding FSUs; only about one viable skin stem cell is required per square centimeter of skin to regenerate. The arrangement of skin FSUs also means that the skin shows a significant 'volume' effect (in this case more of an 'area effect').

## Telangiectasia

Telangiectasia is due to radiation damage of small arteriolar and capillaries. Endothelial cells may live for years and may die mitotic deaths when they attempt to divide. This leads to loss of capillaries and dilatation of surviving vessels. The loss of vessels leads to nutient deprivation of the overlying skin, causing thinning. The thin skin allows easier visualization of the dilated capillaries, giving the clinical syndrome of telangiectasia. Telangiectasia has an $\frac{\alpha}{\beta}$ value of between 3 and 4.
For field sizes of 100 cm2

• The TD10/5 is about 50 Gy
• The TD30/5 is about 59 Gy
• The TD50/5 is about 65 Gy

for the development of telangiectasia, with a latency of about 5 years on average.

## Fibrosis

Radiation may induce the transformation of fibroblasts to fibrocytes. Fibrocytes are active producers of collagen, and this may explain the loss of elasticity and increasing density of the dermis following irradiation. Interaction between endothelial cells and macrophages likely plays a role in this development as well. Fibrosis has an $\frac{\alpha}{\beta}$ value of about 1.9. The latency for fibrosis is about 3 years, and once it occurs it may be progressive.

## Oedema

Loss of lymphovascular endothelial cells can lead to a reduction in lymphatic drainage as vessels become obliterated. This can lead to oedema of the overlying area, in this case the skin.

## Chronic Ulceration / Necrosis

Skin necrosis is a serious complication that arises when there is loss of all epithelial stem cells from an area and inability of surrounding skin to grow into the denuded area. The underlying tissue may be unable to support an epithelial layer due to destruction of blood vessels (either primary or secondary to fibrosis).
Skin necrosis shows a strong volume effect and occurs at doses above telangiectasia:

• TD3/5 is 51 Gy
• TD5/5 is 55 Gy
• TD50/5 is 70 Gy

Smaller fields:

• A 30 cm2 field has a TD3/5 of 57 Gy
• A 10 cm2 field has a TD3/5 of 69 Gy

## Other Late Skin Effects

There are numerous other effects which may be seen, including hyperpigmentation (due to stimulation of melanocytes) or scaling (due to overactivity of basal epidermal cells or loss of skin lubrication (see below)).

## Skin appendages

Skin appendages are not as well studied.

### Hair follicles

Epilation (loss of hair) occurs after very low doses - the threshold for this deterministic effect is about 4 Gy in a single dose. Permanent hair loss occurs with single doses of 10 Gy or more. Fractionated treatment spares hair follicles; hair growth may return eventually even after doses of 40 Gy.

### Skin glands

The eccrine, apocrine and sebaeceous glands of the skin may all be rendered non-functional by radiation with tolerance doses of under 15 Gy. Recovery is possible but function may be permanently lost when doses climb over 30 - 40 Gy in fractionated schedules.

## Summary of Late Skin Toxicity

Skin is comprised of numerous function subunits centres around small vessels which supply the papillary dermis and overlying epithelium. It demonstrates a marked volume effect. Telangiectasia and fibrosis are seen with doses to skin of over 45 Gy and are likely with doses over 65 Gy. Skin necrosis is the most severe late effect and is seen with doses over 55 Gy. The skin appendages are typically less resistant than the epithelium and may suffer from permanent loss with doses that the skin would otherwise tolerate.