Radiation-Induced Skin Fibrosis: Pathogenesis, Current Treatment Options, and Emerging Therapeutics

Abstract

Radiotherapy (RT) has become an indispensable part of oncologic treatment protocols for a range of malignancies. However, a serious adverse effect of RT is radiodermatitis; almost 95% of patients develop moderate to severe skin reactions following radiation treatment. In the acute setting, these can be erythema, desquamation, ulceration, and pain. Chronically, soft tissue atrophy, alopecia, and stiffness can be noted. Radiodermatitis can delay oncologic treatment protocols and significantly impair quality of life. There is currently a paucity of effective treatment options and prevention strategies for radiodermatitis. Importantly, recent preclinical and clinical studies have suggested that fat grafting may be of therapeutic benefit, reversing detrimental changes to soft tissue following RT. This review outlines the damaging effects of RT on the skin and soft tissue as well as discusses available treatment options for radiodermatitis. Emerging strategies to mitigate detrimental, chronic radiation-induced changes are also presented.

Fig. 1.. The proposed mechanism underlying radiation-induced fibrosis (RIF).

A) RT delivers ions that directly induces DNA damage and generates reactive oxygen species (ROS). Damaged cells in the skin and endothelium (colored purple) release cytokines, leading to activation of the innate and adaptive immune systems and recruitment of inflammatory cells. B) Once recruited to the irradiated area, neutrophils release additional inflammatory mediators to sustain inflammation. Lymphocytes and monocytes also migrate to the location of injury, the latter of which differentiate into macrophages. Macrophages, fibroblasts, native endothelial cells, and epidermal cells release transforming growth factor-beta (TGF-β) which stimulates fibroblasts to differentiate into myofibroblasts. C) Myofibroblasts secrete excess amounts of extracellular matrix proteins, leading to increased tissue stiffness and thickness. Over time, RIF ensues and may persist even decades after radiation therapy.