Review article
The radiotherapeutic injury – a complex ‘wound’

https://doi.org/10.1016/S0167-8140(02)00060-9Get rights and content

Abstract

Radiotherapeutic normal tissue injury can be viewed as two simultaneously ongoing and interacting processes. The first has many features in common with the healing of traumatic wounds. The second is a set of transient or permanent alterations of cellular and extracellular components within the irradiated volume. In contrast to physical trauma, fractionated radiation therapy produces a series of repeated insults to tissues that undergo significant changes during the course of radiotherapy. Normal tissue responses are also influenced by rate of dose accumulation and other factors that relate to the radiation therapy schedule. This article reviews the principles of organised normal tissue responses during and after radiation therapy, the effect of radiation therapy on these responses, as well as some of the mechanisms underlying the development of recognisable injury. Important clinical implications relevant to these processes are also discussed.

Introduction

Radiotherapeutic injury is a complex process that occurs in organised tissues, i.e. tissues which comprise a large number of interacting, mutually dependent cellular lineages, as well as a multitude of biologically active extracellular molecules. This perspective is in some contrast to the more traditional (minimalist) approach that considers injury to individual cell lines that can be modelled by cell culture. All organised tissues are capable of mounting reparative responses to injury. This review examines some of these responses and draws attention to some unique phenomena that occur as a result of repetitive injuries – the series of exposures to ionising radiation that make up a course of radiotherapy.

The response of normal tissues to radiotherapy can be viewed as comprising two partially interacting components, each of which is very complex. The first is a process that in many, but not all, respects resembles the healing of traumatic wounds, while being subject to perturbation by the radiation treatment. The second is a set of specific injuries that affect virtually all cellular and extracellular components within the irradiated volume, and that may be responsible for the progression of injury over a period of many years.

The radiotherapy ‘wound’ differs in interesting ways from acute traumatic, thermal or chemical wounds, in which structural tissue damage occurs instantaneously, or nearly so. In contrast to these types of injury, exposure to ionising radiation produces a burst of free radicals, which, while obviously not re-arranging tissue components immediately, not only causes DNA damage, but also alters proteins, lipids, carbohydrates, and complex molecules. While the amount of energy deposited is minimal, each exposure inflicts considerable injury. Another important characteristic of radiation therapy is that it inflicts a series of small tissue insults as each fraction is delivered. In many tissues, each fraction thus contributes to accumulating inflammatory cell recruitment as well as to the accumulation of direct tissue injury. Furthermore, each fraction affects tissue that already exhibits a dynamic spectrum of cellular injury, ongoing repair, inflammation, and other pathophysiologic responses. Therefore, with repetitive radiation exposure, many cellular and molecular responses will be substantially exacerbated, suppressed, or substantially altered compared to the situation after a single exposure to radiation or traumatic injury.

Rate of dose accumulation (RDA) is important to all of these processes and sometimes quite independently of fraction size. First, the timing and magnitude of the inflammatory response to radiotherapy depends on RDA, since inflammatory responses do not ‘fade’ (or cease) within hours of each radiation exposure as ‘sublethal’ cellular damage generally does. Therefore when a course of radiotherapy involves rapid dose accumulation (i.e. is ‘dose intense’), regardless of how it is fractionated, the inflammatory response also accumulates quickly. This may be important because aspects of the inflammatory response are capable of greatly amplifying radiation-induced microvascular injury. Second, suppression of reparative tissue responses to injury depends on RDA, since such responses, be they re-epithelialisation or the formation of ‘granulation’ tissue, include vigorous proliferation of several cell lineages. Therefore, the more rapidly dose is delivered, regardless of fraction size, the more effective the suppression is.

While what appears as full ‘healing’ of the sub-acute radiotherapy injury may ensue, perturbation of the reparative processes affect the integrity of the repair. It is well known that healed traumatic wounds ‘remodel’ continuously for years following injury. In contrast, the viability of irradiated tissues and/or their capacity to remodel is often compromised by lasting cellular dysfunction or changes in the supporting (mesenchymal) stroma. Inflammation may further stress irradiated epithelial lined tissues if failure of the reparative process results in insufficient epithelial barrier function. Coupled with this, and sometimes compounded by self-perpetuating ‘reactive’ fibrosis, progressive parenchymal cellular depletion with ‘replacement’ fibrosis completes a picture that is recognised as delayed radiation injury.

The main part of this review deals with organised tissue responses to radiotherapy, the effect of radiotherapy on these responses, and the development of recognisable injury. The final part of the review discusses some important clinical implications of these observations. To assist readers with some of the analogies and comparisons that are drawn in this review, a simplified schematic diagram of processes involved in healing of traumatic wounds is presented in Fig. 1. While it will be immediately apparent that, there is little requirement for haemostasis and tissue closure by scar formation in radiotherapy injury as there is in a traumatic wound, it will be equally obvious that many processes that contribute to healing of traumatic wounds are also involved in early and delayed normal tissue responses to radiation.

Examination of radiotherapeutic injury from this perspective is helpful because it provides explanations both for the clinical and pathological features of early and delayed injuries. An understanding of the mechanisms that contribute to organised tissue injury together with an appreciation of the reparative processes that occur in response to this injury, may assist in the development of avoidance and prevention strategies.

Section snippets

The induction of a ‘wound healing’ response

Higher vertebrates respond to traumatic tissue injury by initiating a sequence of overlapping events that includes activation of the coagulation system, inflammation, epithelial regeneration, granulation tissue formation, and matrix deposition and remodelling. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors.

While the response to radiotherapeutic injury of normal tissues differ in many ways from a

Part 2 – clinical implications

The recognition that non-lethal functional cellular injuries and tissue responses such as inflammation, reparative processes, and fibrosis contribute to delayed radiation injury over and above the contribution made by progressive cellular depletion leads to a revised framework within which radiation injury may be classified [28] (see Table 3).

This recognition is compatible with the recent observation by Jung et al. [76] that the rate of development of late effects does not plateau out over

Acknowledgements

We should like to thank Debbie Wright for her expert help in assembling the manuscript and the series of overviews that it originated from. Supported by the Hunter Medical Research Institute and the National Institutes of Health (grants CA-71382 and CA-83719).

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