Actinic keratosis as a premalignant lesion: Systematic review and meta-analysis of topical field–directed therapy versus vehicle/placebo.

Abstract

e21568 Background: Actinic keratosis represents a premalignant lesion within the field cancerization pathway and isassociated with an increased risk of keratinocyte carcinoma. Topical field-directed therapies arecommonly used to treat photodamaged skin; however, comparative vehicle-controlled randomizedevidence on complete clearance outcomes has not been consistently synthesized. A meta-analysis wasconducted to evaluate the efficacy of topical field-directed therapies (5-fluorouracil) versusvehicle/placebo in achieving complete lesion clearance. Methods: A systematic search was conducted in PubMed, Embase, and the Cochrane Central Register ofControlled Trials from inception to January 2026 to identify randomized vehicle- orplacebo-controlled trials evaluating topical field-directed therapies (5-fluorouracil) for actinickeratosis. Eligible studies enrolled adults with clinically diagnosed actinic keratoses and reporteddichotomous efficacy outcomes or adverse events. Three independent randomized trials comprising atotal of 1,422 participants were included. Pooled analyses were performed using random-effectsmodels, and results were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Results: Three randomized vehicle-controlled trial datasets were included. For complete clinical clearance,topical field-directed therapy was associated with a significantly higher likelihood of complete lesionclearance compared with vehicle/placebo (RR 2.90; 95% CI 1.76–4.77; P < 0.0001; I² = 58%), with atotal of 276 complete clearance events among 631 patients receiving active topical therapy versus 88events among 539 patients in the vehicle/placebo group. The direction of effect was consistent acrossthe two largest trials, which contributed the majority of the pooled weight. Conclusions: Topical field-directed therapy significantly increases the probability of complete clinical clearance ofactinic keratosis compared with vehicle/placebo. Given that actinic keratosis represents apremalignant manifestation of field cancerization within the keratinocyte carcinoma pathway, theseresults support topical field therapy as an effective strategy for controlling the premalignant field inhigh-risk populations. However, the available evidence is limited by the number of randomized trialsand clinical heterogeneity, underscoring the need for additional well-designed studies to further defineoptimal treatment strategies and long-term oncologic relevance. Complete clearance emerges as aclinically meaningful dichotomous endpoint for evaluating interventions targeting field cancerizationin skin oncology.