Efficacy of 5-Fluorouracil 4% Cream in the Treatment of Hyperkeratotic Actinic Keratosis: A Single-Center Retrospective Real-World Study

Abstract Introduction Actinic keratosis (AK) is recognized as the main precursor of cutaneous squamous cell carcinoma (cSCC). Given the unpredictable potential for progression, current guidelines recommend treating all AKs, irrespective of their clinical grade. However, many approved treatments are not indicated for hyperkeratotic AKs. Among topical therapies, 5-fluorouracil (5-FU) 4% cream (Tolak®/Tolerak®; Pierre Fabre) is a chemotherapeutic agent that has shown excellent results in treating non-hyperkeratotic AKs on the face, ear, and scalp, both in clinical trials and real-life experiences. However, its effectiveness in managing hyperkeratotic AKs remains unexplored. Methods A retrospective, single-center study was conducted at the Dermatology Unit of the University of Messina, Italy, between September 2024 and March 2025. The study included 66 hyperkeratotic AK lesions in 19 consecutive patients, treated with 5-FU cream for 28 consecutive days. Results At the 3-month follow-up, total clearance (complete lesion resolution) was observed in 54.5% of hyperkeratotic lesions, while partial clearance (> 75% lesion reduction) was recorded in 24.2%. The treatment demonstrated a good safety profile, with good patient tolerability. Among local skin reactions (LSRs), erythema was the most frequently observed, occurring in 89.5% of patients, followed by stinging, which was reported in 73.6% of cases. No patient discontinued the treatment as a result of the onset of adverse events. Conclusions Our findings, albeit initial, support the efficacy and safety of 5-FU 4% cream for the treatment of hyperkeratotic AKs.