Radiotherapy-Induced Skin Fibrosis: Pathophysiology, Emerging Therapeutics, and the Role of Dermatology

Abstract

Radiotherapy-induced skin fibrosis is a chronic progressive complication of radiotherapy that impairs function, aesthetics, and quality of life yet remains under-recognized and undertreated. While acute cutaneous toxicities are typically transient, chronic sequelae such as fibrosis, lymphedema, atrophy, telangiectasia, and dyspigmentation reflect uncontrolled tissue remodeling driven by sustained inflammation and fibroblast activation. Ionizing radiation generates reactive oxygen species that initiate vascular and epithelial injury, trigger immune infiltration, and perpetuate a cycle of transforming growth factor-β-driven myofibroblast differentiation, epithelial-to-mesenchymal transition, extracellular matrix deposition, and epigenetic reprogramming. Predicting and grading radiotherapy-induced skin fibrosis remains difficult: physician-reported scales lack sensitivity, and emerging imaging modalities and candidate tissue biomarkers require validation. Therapeutic strategies include pentoxifylline with vitamin E, oral statins, corticosteroids, fractional CO₂ and pulsed dye lasers, autologous fat grafting with adipose-derived stem cells, and manual therapies, each with varying efficacy. Investigational approaches such as deferoxamine, microneedling, and mesenchymal stem cell-based interventions show antifibrotic and regenerative potential, while candidate therapies including topical statins, antioxidants, timolol, tamoxifen, and colchicine remain untested. Despite the rising burden among cancer survivors, many patients do not receive a dermatologic evaluation, and consensus guidelines are limited. Dermatology should lead multi-modal efforts to integrate systemic, topical, and procedural interventions, develop standardized diagnostic frameworks, validate biomarkers, and conduct skin-specific clinical trials. Greater involvement of dermatologists in survivorship care, early referral, and advocacy for policy and funding will be essential to address radiotherapy-induced skin fibrosis and improve patient outcomes.