Oral Retinol, Alone or Combined with Medical Photoprotection, in Patients with Actinic Keratosis: A Randomized, Open-Label, Prospective, Multicentric Study

Actinic keratosis (AK) is a chronic ultraviolet-induced condition with potential progression to squamous cell carcinoma. This study assessed the efficacy and tolerability of oral retinol, alone or combined with broad-spectrum medical photoprotection containing piroxicam, in patients with mild-to-moderate AK. In this multicenter, prospective, randomized, open-label study, 117 patients with up to six AK lesions were assigned to oral retinol 50,000 international units (IU)/day (group A), oral retinol plus medical photoprotection (group B), or standard photoprotection recommendations (group C). Treatment lasted 6 months, followed by 3 months of follow-up. Assessments were performed at baseline and at months 3, 6, and 9. The primary endpoint was change in Actinic Keratosis Area and Severity Index (AKASI). Secondary outcomes included global clinical efficacy, lesion clearance, tolerability, and exploratory line-field confocal optical coherence tomography findings. All 117 patients were included in the intention-to-treat analysis, and 99 in the per-protocol analysis. AKASI scores decreased significantly in group A at month 6 by − 19.3% (mean difference (MD) 0.61, 95% confidence interval (CI) 0.11–1.11; p < 0.05) and at month 9 by − 22.5% (MD 0.71, 95% CI 0.18–1.25; p < 0.01). In group B, significant reductions were observed at all time points (T3: − 24.1%; MD 0.90, 95% CI 0.42–1.39; p < 0.0001; T6: − 34.9%; MD 1.31, 95% CI 0.86–1.76; p < 0.0001; T9: − 38.8%; MD 1.45, 95% CI 0.95–1.95; p < 0.0001). No significant changes occurred in group C. Reductions were earlier and greater with the combined strategy. Global clinical efficacy was rated good or very good in 69% of patients in group A and 88% in group B, while lesion clearance rates were 56% and 82%, respectively. Tolerability was generally good, and no treatment-related adverse events were formally recorded. In the imaging substudy, significant reductions in epidermal and stratum corneum thickness occurred only in group B. Oral retinol combined with medical photoprotection was associated with earlier and greater improvements than oral retinol alone or standard photoprotection recommendations. These findings support further controlled studies to confirm efficacy and clarify the contribution of each intervention. Trial registration number ISRCTN42565762, retrospectively registered on 18 May 2026.