Impaired wound healing after radiation therapy: A systematic review of pathogenesis and treatment

Abstract

Background: Radiotherapy is a common cancer treatment, but often results in unintended injury to overlying skin and contributes to poor wound healing. The mechanisms underlying these changes are complex, and existing treatment is limited. We aimed to systematically review the literature on the pathogenesis, management, and experimental treatment of delayed wound healing following radiation therapy. Study Design/Methods: A literature search was performed following PRISMA-P guidelines. PubMed and the Cochrane Library were queried for full-text English articles published up to 2016 by using key search terms including “radiotherapy” and “wound healing.” Additional resources were retrieved from reference lists. The selected articles discussed mechanisms of pathogenesis, current management, and experimental treatment of radiation-induced skin injury. These are reported as a qualitative synthesis of the literature from the authors' perspective. Results: The literature search yielded 442 articles, of which 93 were included in this review. Ionizing radiation causes DNA damage by direct strand breaks and oxygen-derived free radicals. This insult results in cellular alterations that underlie mechanisms of delayed wound healing. Prominent theories underlying pathogenesis include cellular depletion, stromal cell dysfunction, aberrant collagen deposition, and microvascular damage. Pro-inflammatory cytokines and free radical cascades contribute to chronic radiation damage, with transforming growth factor beta-1 (TGF-β1) implicated as a key player in the process of fibrosis. At present, radiation injury is managed medically with conventional wound care with minimal success and limited evidence-based data. Surgical management with local or free flap transfer is often compromised by poor surrounding tissue and recipient vasculature. Experimental treatment models are emerging that target mechanisms of pathogenesis. These modalities include stem cell repletion, antioxidant therapy, TGF-β1 modulation, and implantable biomaterials. Conclusion: Pathogenesis of delayed wound healing and fibrosis following radiotherapy is a complex, interdependent process involving cellular depletion, extracellular matrix changes, microvascular damage, and altered pro-inflammatory mediators. Current treatment is limited, and more Level I studies are needed to develop best-practice recommendations. Investigatory treatment options targeting specific mechanisms of injury may offer potential solutions to this significant clinical and surgical problem.

Keywords

• Skin
• Ionizing radiation
• Wound healing
• Radiation fibrosis
• Radiation therapy
• Systematic review