Abstract
Photodynamic therapy (PDT) has become a widely used modality for treating actinic keratosis (AK) and non-melanoma skin cancers (NMSC), as well as other inflammatory or infectious diseases. Despite its efficacy, limitations such as incomplete responses and pain have motivated the exploration of protocol enhancements. This review examines the clinical and biological rationale for light fractionation-dividing the total light dose into two separate exposures with a dark interval-as a strategy to improve PDT outcomes. We reviewed preclinical and clinical studies evaluating fractionated illumination using 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL). The findings consistently demonstrate superior efficacy of fractionated schemes, particularly with ALA, showing higher complete response rates in AK, superficial basal cell carcinoma (sBCC), and Bowen's disease (BD), and improved long-term tumor control compared to single illumination. The better outcomes are attributed to increased reactive oxygen species (ROS) generation following tissue reoxygenation during the dark interval and greater susceptibility of partially damaged cells to subsequent illumination. Fractionated PDT also shows a favorable safety and cosmetic profile. These results support considering light fractionation protocols as a standard approach for optimizing PDT efficacy in dermatologic oncology, particularly in lesions with limited depth and high recurrence risk.