Sequential 5-Fluorouracil–Photodynamic Therapy: A Mechanism-Based Approach to Actinic Keratosis

BACKGROUND: Actinic keratosis (AK) is a common premalignant condition arising from chronic ultraviolet exposure and frequently occurs within fields of sun-damaged skin that harbour subclinical dysplasia. OBJECTIVE: To summarize the mechanistic rationale, clinical evidence, safety profile, and practical considerations for a sequential regimen of short-course topical 5-fluorouracil (5-FU) pretreatment followed by daylight-mediated photodynamic therapy (dPDT) for field-directed management of AK. METHODS: We performed a narrative synthesis of randomized controlled trials, split-site studies, mechanistic investigations and cohort reports identified through comprehensive searches of major biomedical databases. RESULTS: An intra-individual randomized trial demonstrated that pretreatment with 4% 5-FU cream prior to daylight-PDT achieved superior overall clearance 87% versus 74% especially in thicker (grade II) lesions. Across the reviewed studies, the sequential use of 5-fluorouracil followed by daylight photodynamic therapy achieved higher rates of complete lesion clearance, particularly in grade II cases. These benefits were sustained in 12 months, with lower recurrence rates and strong patient satisfaction. While the combination approach was linked to temporary redness and scaling, these side effects were mild and did not result in treatment discontinuation in the reported trials. CONCLUSIONS: Short-course topical 5-FU pretreatment before dPDT is a biologically plausible and clinically promising strategy to improve lesion and field clearance in AK, particularly for moderately thick lesions. Larger multicentre randomized trials with standardized protocols and longer follow-up are required to define optimal dosing, timing, and applicability to hyperkeratotic high-grade lesions.