Intensity of Local Skin Reactions During 5-Fluorouracil Treatment Related to the Number of Actinic Keratosis Lesions: A Post Hoc, Exploratory Analysis

Plain Language Summary In order to prevent recurrence of actinic keratosis lesions and their progression to invasive squamous cell carcinoma, topical treatment of actinic keratosis often involves treating the field of cancerisation to clear visible and subclinical lesions. The occurrence of local adverse skin reactions during treatment can affect patient adherence to therapy and therefore compromise efficacy. A thorough understanding of the relationships between changes in lesions, actinic keratosis remission and tolerability of topical treatments over time is necessary to manage patient expectations, ensure treatment adherence and optimise clinical outcomes. This exploratory study used pooled data from two pivotal phase III studies to compare local skin reaction severity between 5-fluorouracil 4% cream applied once daily and 5-fluorouracil 5% cream applied twice daily, then to examine the relationship between the severity of local skin reactions during treatment and the number of actinic keratosis lesions at baseline. Local skin reactions appeared to be more severe in patients with more than 10 actinic keratosis lesions at baseline than in those with 5 to 10 lesions. Using a cut-off value of 10 lesions pre-treatment, healthcare practitioners can forewarn patients accordingly of potentially more severe local adverse skin reactions in order to motivate them to complete their treatment, thus ensuring treatment efficacy. If patients are likely to experience intolerable severe skin reactions, practitioners can plan to introduce an appropriate rescue treatment. Introduction Actinic keratoses (AK) are epithelial lesions caused by chronic skin exposure to ultraviolet light that can progress into squamous cell carcinoma. Although several treatments are effective, they are associated with severe skin reactions, which might be related to the extent of the disease. This study aimed to examine the relationship between the severity of local skin reactions during treatment with 5-fluorouracil 4% cream and the number of AK lesions at baseline. Methods This post hoc analysis pooled data from two multicentre randomised phase III studies (HD-FUP3B-048, HD-FUP3B-049) in patients with AK treated with topical 5-fluorouracil 4% once daily (OD) or 5% twice daily (BID) for 4 weeks. First, we compared the severity, assessed using a numerical rating scale, of the local skin reactions between 5-fluorouracil 4% and 5%. Then, we investigated the relationship between the number of lesions at baseline and severe skin reactions with 5-fluorouracil 4% OD. Results Safety data were included from 397 patients who had received 5-fluorouracil 4% (348 in study HD-FUP3B-048, 49 in study HD-FUP3B-049) OD and 342 (HD-FUP3B-048) who had received 5-fluorouracil 5% BID. For most skin reactions, severe ones were more common in patients treated with 5-fluorouracil 5% cream BID than in those treated with 5-fluorouracil 4% cream OD (P < 0.05). With 5-fluorouracil 4% OD, the incidence of severe erythema was significantly higher in patients with at least 10 lesions (46%) than in patients with 5-10 lesions (28%; P < 0.001). Similar results were observed for the other local skin reactions. Conclusion Treatment with 5-fluorouracil 4% cream OD was associated with less severe local skin reactions than 5-fluorouracil 5% BID. The number of AK lesions at baseline seems to have predictive value regarding the severity of local skin reactions that appear during treatment.

Automated summary

This study compared the severity of local skin reactions between 5-fluorouracil 4% cream applied once daily and 5% cream applied twice daily, and found that patients with more than 10 actinic keratosis lesions at baseline tend to experience more severe skin reactions during treatment. The number of lesions at baseline has predictive value in determining the severity of local skin reactions during treatment with 5-fluorouracil 4% cream.