Radiotherapy in Li-Fraumeni Syndrome: From Biological Concern to Personalized Clinical Decision-Making

Li-Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome caused by germline pathogenic variants in <i>TP53</i>. It is characterized by a high risk of developing malignancies throughout life, often at an early age. Because p53 is involved in cellular responses to DNA damage, the use of radiotherapy in this population has raised long-standing clinical concerns regarding potential late effects. This narrative review outlines key biological considerations related to radiation exposure in <i>TP53</i> mutation carriers and summarizes the clinical experience reported with radiotherapy in patients with LFS. From a biological perspective, altered p53 function may influence how cells respond to ionizing radiation and how damaged cells are managed. These considerations have led to caution when considering radiotherapy in this setting. From a clinical perspective, the available literature remains limited and largely retrospective. Published reports describe variable outcomes after radiotherapy, including cases of secondary malignancies developing within previously irradiated regions, as well as cases without apparent long-term complications. Overall, clinical responses and long-term outcomes appear heterogeneous. In the absence of prospective data, radiotherapy in LFS should not be viewed as an absolute contraindication. Its use may be considered in selected clinical situations after careful multidisciplinary discussion. Decisions should balance the expected oncologic benefit with potential long-term risks and available alternatives. When radiotherapy is used, careful treatment planning to limit normal tissue exposure and long-term follow-up are essential components of patient care.