Radiation-Induced Fibrosis (RIF) in Head and Neck Squamous Cell Carcinoma (HNSCC): A Review

Radiation-induced fibrosis (RIF) refers to the aberrant and continuous induction of myofibroblast-mediated wound healing in response to radiation therapy (RT) and occurs in up to 50% of head and neck squamous cell carcinoma (HNSCC) patients post-RT. Frontline treatment consists of an anti-inflammatory agent, pentoxifylline, in combination with an antioxidant, Vitamin E, (PENTOX) along with palliative care agents such as corticosteroids, non-steroidal anti-inflammatory agents, muscle relaxants (i.e., botulinum toxin A), or physical therapy for alleviation of symptoms such as pain, inflammation, and lymphedema. However, while efficacious in stabilization and palliation of disease, PENTOX is one of the only established agents with confirmed anti-fibrotic effects in HNSCC. Alternative therapies such as hyperbaric oxygen therapy or superoxide dismutase show efficacy in alleviating acute radiation toxicities but lack a substantial reduction in fibrotic burden. Furthermore, experimental investigations into natural antioxidants, anti-fibrotic agents approved for idiopathic pulmonary fibrosis, mesenchymal stem cell therapy, and general nutritional support, indicate anti-RIF potential, but studies in HNSCC specifically are lacking. This review aims to characterize the pathogenesis of RIF development in the HNSCC disease setting and summarize promising anti-fibrotic agents under investigation for radiation-induced toxicities.