Simple SummaryActinic keratosis (AK) is a premalignant skin lesion caused by chronic sun damage, which usually arises in older people on chronically sun-exposed areas of the body, such as the face, scalp, ears, neck, back of the forearms and hands. Actinic keratosis rarely occurs as a single lesion; most often it can involve multiple lesions in a field of cancerization. Since the AKs may progress to invasive squamous cell carcinoma, treatment of any AK regardless of clinical severity is strongly recommended. The goals of AK therapy are to eradicate clinical and subclinical lesions, prevent the progression into invasive squamous cell carcinoma, provide a good cosmetic outcome and reduce the risk of relapses. Multiple treatment options are available for this condition; however, no gold standard therapy has been established. A novel formulation of 4% 5-Fluorouracil with once daily application proved to be a highly effective and safe treatment for multiple actinic keratoses.AbstractBackground: Actinic keratosis (AK) is one of the most common skin diseases, with a low risk of progression into invasive squamous cell carcinoma. We aim to assess efficacy and safety of a novel formulation of 5-Fluorouracil (5-FU) 4% with once daily application for the treatment of multiple AKs. Methods: A pilot study was performed on 30 patients with a clinical and dermoscopic diagnosis of multiple AKs, enrolled between September 2021 and May 2022 at the Dermatology Departments of two Italian hospitals. Patients were treated with 5-FU 4% cream once daily for 30 consecutive days. The Actinic Keratosis Area and Severity Index (AKASI) was calculated before starting therapy, and at each follow-up, to assess objective clinical response. Results: The cohort analyzed included 14 (47%) males and 16 (53%) females (mean age: 71 ± 12 years). A significant decrease in AKASI score at both 6 and 12 weeks (p< 0.0001) was observed. Only three patients (10%) discontinued therapy, and 13 patients (43%) did not report any adverse reactions; no unexpected adverse events were observed. Conclusions: In the setting of topical chemotherapy and immunotherapy, the new formulation of 5-FU 4% proved to be a highly effective treatment for AKs and field cancerization.