Randomized comparative study of 5-Fluorouracil 4%, tirbanibulin, and photodynamic therapy for relapsing actinic keratoses

Background: Actinic keratosis (AK) reflects a field cancerization process in chronically sun-damaged skin, and relapse after diclofenac therapy is a frequent clinical scenario. Field-directed treatments such as 5-fluorouracil (5-FU), tirbanibulin, and photodynamic therapy (PDT) are widely used, yet comparative data in post-diclofenac relapse and the contribution of reflectance confocal microscopy (RCM) to therapeutic monitoring remain limited. Objectives: To compare the clinical efficacy, tolerability, and subclinical response of 5-FU 4%, tirbanibulin 1%, and PDT in relapsing AK of the scalp, integrating RCM imaging to assess field response. Methods: A prospective randomized (1:1:1) study was conducted in 45 patients who previously achieved complete clearance with diclofenac 3% and relapsed within 12 months. Endpoints included clinical clearance at 12 weeks, RCM normalization, recurrence at 6 months, and local skin response (LSR) severity. Results: Twelve-week clearance rates were 73.3% for 5-FU, 66.7% for tirbanibulin, and 80.0% for PDT (p=0.711). RCM normalization occurred in 66.7%, 60.0%, and 73.3% of patients, respectively (p=0.741). Recurrence among responders at 6 months was low and comparable (9.1%, 10.0%, and 8.3%; p=0.991). Tirbanibulin showed significantly lower LSR scores versus 5-FU and PDT (p<0.001), indicating superior tolerability. Conclusions: Short-term efficacy of 5-FU, tirbanibulin, and PDT was comparable, while tolerability differed markedly. Tirbanibulin demonstrated the most favorable inflammatory and cosmetic profile, whereas 5-FU and PDT may be preferred when a more intense field effect is desired. RCM detected subclinical persistence in select cases and may serve as an adjunctive imaging tool for monitoring and guiding retreatment in field cancerization.