N orm al-Tissue Effects

Normal tissues and tumours show a radiation response at a rate proportional to their rate of proliferative turnover. For instance, the mucosa of the respiratory and digestive tract, which is actively proliferative, develops a detectable reaction within two or three weeks of first exposure to a course of radiotherapy. However, slowly proliferating tissues such as connective tissue, kidney, cartilage, bone, lung and oligodendricites respond slowly to irradiation with signs of damage only months or years after exposure. The length of time to express 90% of the ultimate frequency of moderate or severe complications can be as long as 3.2 years and 4.7 years for the late effects fibrosis and telangiectasia respectively (Bentzen et a l 1989).

Normal-tissue effects are classified as acute if they manifest during the first 90 days after radiotherapy, subacute if they develop within 1 to 3 months postirradiation and late sequelae thereafter (Dorr 1998). In general, late-tissue effects are regarded as more important than acute effects because of their progressive and irreversible character. However, an acute side effect may lead to a consequential late effect (§1.4.2: Zimmermann et a l 1998a) or an interruption of the treatment course and therefore a decrease in local tumour control (Fowler and Lindstrom 1992).

Laboratory experiments have led to the conclusion that whereas both fraction size and overall treatment time determine the acute response, fraction size is the dominant factor in determining late effects with the overall treatment time having little influence (Hall 1993). In this respect there is a dissociation between the risk of acute and late effects (§1.4.2). Several studies in both humans and animals have suggested that the severity and expression of the late effect of fibrosis in the lung are, at least in part, genetically determined (Geara et a l 1998, Franko et a l 1991).

It has been suggested that expression of a specific chnical endpoint is related to cellular radiosensitivity of a specific target cell. Acute radiation lesions are thought to be a direct consequence of parenchymal cell loss. Late radiation damage to a number of normal tissues is also characterised by depletion of parenchymal cells, as well as a marked

increase in the fibrotic tissue component. This is a consequence of functional perturbations involving both parenchymal and non-parenchymal elements, most

noticeably the vasculature (Rezvani etal. 1995).

Acute effects include nausea, mucositis, alopecia and myelosuppression, interstitial inflammation and erythema. They are usually self-limiting and recovery takes place provided that the tolerance dose has not been exceeded. Acute inflammation comprises of vasodilation, fluid exudation and leukocyte migration at the sites of inflammatory lesions (Narayan and Cliff 1982). Inflammatory cytokines induce a number of adhesion molecules which bind leukocytes and lymphocytes to the endothehum (reviewed in Luster 1998). It has been shown that the early change noted in vivo, following localised irradiation of the kidney is leukocyte adhesion to the endothehal cells of the glomerular capillary loops (Jaenke etal. 1993).

The effect of radiation on the vasculature is of importance because blood vessels form an integral part of nearly all normal tissues. The potential target cells in the vasculature, the endothelial cells and smooth muscle cells, have a low turnover and so damage to such cells is only expressed slowly after irradiation. However, it has been shown that a single dose of 10 Gy alters the structure and function of normal-tissue microvasculature networks significantly at 3, 7, and 30 days postirradiation (Roth et al. 1999).

Initial changes in the vasculature after 2-A months are associated with the loss of endothelial cells. This results in abnormal proliferation of viable cells leading to the occlusion of vessels and a reduction in the size of the capillary bed. There may be local oedema (accumulation of fluid) possibly as a consequence of the local leakage of plasma. This vascular-tissue damage may be the major element determining the overall late-tissue damage after irradiation. Many investigators have noted increased vascular permeability associated with oedema after irradiation of the kidney, lung, thorax, brain and skin (Moosavi et al. 1977, Evans et al. 1986, Law and Thomlinson 1978). Later changes in the vasculature are associated with the loss of smooth muscle cells. The timing of these later changes are more variable (7-18 months) than the earlier effects related to the loss of endothelial cells.

The consequences of these well established changes varies from tissue to tissue and depends on complex adaptations and physiological relationships which are not fully understood. However, they could partly explain the variation in latency noted for the development of late effects in different tissues (Hopewell et al. 1986).

Radiation-induced fibrosis is a common late reaction in radiotherapy. Fibrotic lesions following radiotherapy have been described in many tissues, including skin, lung, heart,

kidney and liver (Jaenke et a l 1993, Rezvani et a l 1995). A review of the cellular basis of fibrosis has been provided by Rodemann and Bamberg (1995) who concluded that it is due to an interplay of cellular and molecular events between several cell systems engaged in a fibrotic reaction. The fibrotic reaction is typified by increased interstitial collagen disposition, thickening of vascular walls and vascular occlusions. Histological examinations of fibrotic lesions have revealed that fibrotic tissue contains infiltrating inflammatory cells, fibroblasts and larger amounts of various extracellular matrix components (§3.4.2). In fibrotic tissues, an enhanced synthesis and deposition of the interstitial collagens, fibronectin and proteoglycans have been described, and this has been interpreted as the result of the radiation-induced modulation of the fibroblast cell system (§3.4.1: Tzaphlidou et a l 1997). Studies in the lung have shown that radiation induces the synthesis of various cytokines, leading to cellular infiltration and fibroblast stimulation and enhanced collagen synthesis (Gauldie et a l 1993). In particular, a pivotal role for the infiltration of CD4+ T-cells and consequent excessive deposition of matrix proteins has been suggested in the development of pulmonary pneumonitis preceding lung fibrosis (Westermann e ta l 1999).

Growth factors and cytokines expressed during wound healing are thought to play a major role in regulating the molecular mechanisms leading to the expression of late- radiation lesions. Elevation of cytokine production starts immediately following irradiation and persists until the pathological signs of fibrosis are apparent (Rubin et a l

1995). Several cytokines including TGF-p and IL-4 have been proposed as fibrosis- promoting cytokines in lung tissue (§3.4.2: Buttner et a l 1997, Raynal et a l (1997).

There are a number of reports in the literature identifying both endogenous and exogenous factors that are associated with an increased risk of radiotherapy-related morbidity (reviewed in Zimmermann e ta l 1998b). It is likely that most of these do not cause a change in the cytotoxicity of radiation, but rather they modify one or more of the steps along the pathogenic pathway, leading to a modulation in expression of injury at the tissue/organ level (Bentzen and Overgaard 1994).

The most important endogenous factors to modify both acute and late-tissue response are metabolic or other diseases leading to macro- or microangiopathia, collagen diseases and immune diseases (§7.2.1). However their influence is largely unquantified, and is dependent on the severity of the disease (Morris and Powell 1997, Ross et a l 1993). Considering exogenous factors the most important are smoking, alcohol, nutrition, hygiene and medical therapies. For example, surgery can increase the risk of adhesions, strictures, fistulae or tissue necrosis. Chemotherapy has been increasingly implicated in late sequelae and can reduce, often substantially, the radiation tolerance of such tissues

as the CNS, auditory nerves, liver, heart, lungs, kidneys and even the fibroadipose tissues of the breast (Withers 1986).