Mechanisms of Radiation-Related Toxicities

Introduction

Radiotherapy comprises the delivery of ionizing radiation, most commonly in the form of X-rays, for the treatment of malignant or benign neoplasms. Radiotherapy induces DNA damage either through direct ionization or through the generation of intermediary reactive oxygen species. Left unrepaired, this damage can lead to normal and tumor cell death via apoptosis, mitotic catastrophe, autophagy, or terminal growth arrest/senescence. Deficiencies in DNA repair, a hallmark of some cancers, can sensitize these tumors to death after irradiation, in part accounting for the favorable therapeutic ratio of radiotherapy. However, DNA repair within normal cells can be incomplete or can be overwhelmed by the dose of radiotherapy delivered, leading to the development of radiation-induced toxicities.

Types of Radiation-Related Toxicities

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  Radiotherapy is a local treatment and therefore adverse effects are generally expected within tissues in closest proximity to the irradiated volume. For example, radiotherapy to the pelvis may result in cystitis, enteritis, proctitis, or bone marrow suppression, but it will not typically cause toxicity in distant organs (e.g., lung). Similarly, in the treatment of pituitary adenomas, cumulative dose to the optic nerves and chiasm will be the major consideration during the treatment planning process to prevent optic neuritis or subsequent blindness. In addition to direct organ damage, there is a risk of secondary malignancy postirradiation. The relationship between the distance from the irradiated volume and risk of secondary malignancy is represented by an inverted U-shape. That is, the risk is lower in the high-dose irradiated volume, increases at intermediate distances from the target volume within a relatively lower dose region, and decreases at greater distances from the treated organ (e.g., increased risk of breast cancer after radiation for mediastinal Hodgkin’s lymphoma).

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  Radiation toxicities are generally categorized as acute, occurring during or within a few weeks of radiotherapy, or late, occurring months to years after treatment. Acute toxicities are mainly mediated by the adverse effects of radiotherapy upon the endothelium, leading to vascular permeability, edema, and lymphocyte adhesion and infiltration. Soon after irradiation, endothelial cells have changes in their physiological appearance and exhibit alteration in synthesis and secretion of growth factors, chemoattractants, and injury markers such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. This process produces an inflammatory response resulting in the recruitment and activation of neutrophils and eosinophils, which culminates in endothelial apoptosis mediated by the activation of sphingomyelinases, the generation of ceramide, and the activation of various caspases.

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  Late toxicities are primarily attributed to the depletion of tissue-specific stem cells and the generation of fibrosis through the excessive production of fibrocytes. Although the inciting molecular reactions take place shortly after radiation exposure, the cellular events and tissue remodeling processes take place over a period of years. Ionizing radiation also induces premature terminal differentiation of progenitor fibroblasts to fibrocytes through an imbalance of inflammatory regulators, particularly transforming growth factor (TGF)-β. TGF-β overexpression has been linked to late effects throughout many organ sites, attributed to the induction of excess collagen synthesis and the inhibition of matrix metalloproteinases. This excessive fibrosis also leads to late vascular effects including capillary collapse, thickening of basement membrane, telangiectasias, and loss of stem cell clonogenic capacity. Tissue-specific stem cells have been shown to reverse this process by normalizing proinflammatory cytokine levels, promoting revascularization, and upregulating antioxidant enzymes, assuming they remain intact after exposure to radiotherapy.