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. 2025 Feb;15(2):307-321.
doi: 10.1007/s13555-024-01336-4. Epub 2025 Jan 16.

Association Between Local Skin Reactions and Efficacy with 5-Fluorouracil 4% Cream in Actinic Keratosis: A Post-Hoc Analysis of Two Randomised Clinical Trials

Markus V Heppt  1   2   3 , Kilian Trin  4   5 , Anne-Cécile Mille  6 , Mélanie Groc  7 , Alain Delarue  4   8 , Nathalie Bégeault  9
Affiliations

Association Between Local Skin Reactions and Efficacy with 5-Fluorouracil 4% Cream in Actinic Keratosis: A Post-Hoc Analysis of Two Randomised Clinical Trials

Markus V Heppt et al. Dermatol Ther (Heidelb). 2025 Feb.

Abstract

Introduction: Topical 5-fluorouracil (5-FU), 5% or 4% cream, is recommended among first-line treatments for actinic keratosis (AK). Local skin reactions (LSRs) are an expected and transient response to treatment with 5-FU but can lead to treatment discontinuation when severe. This analysis aimed to investigate whether the severity of LSRs during the treatment was associated with lesion clearance assessed 4 weeks after completing treatment.

Methods: This post hoc analysis pooled data from two randomised clinical trials (HD-FUP3B-048 and HD-FUP3B-049). Only patients treated with once-daily 5-FU 4% for 4 weeks were considered. Analyses included LSR severity at week 2 and 4 and clearance 4 weeks after completing treatment (week 8). Analysed LSRs were erythema, scaling, oedema, crusting, erosions, stinging and pruritus, which were each categorised as mild, moderate, severe or none. Response was categorised as complete clearance (CC; clearance of all lesions), partial clearance (PC; ≥ 75% clearance) or no clearance (NC; < 75% or for subgroup analyses NC < 100%).

Results: Data from 397 patients were included. The median number of AK was 11 (lower quartile Q1 = 7 and upper quartile Q3 = 18) and grades were mild to moderate (86.4% of patients) and severe. At week 8, 321 patients (80.9%) had CC/PC and 76 (19.1%) had NC. Patients who achieved CC/PC had, at baseline, more lesions, a more severe disease and lesions preferentially on the ears/face than patients with NC. In adjusted logistic regression analyses and across all LSR grades, CC/PC at week 8 was associated with occurrence of erythema, oedema, crusting and stinging at week 2 and all LSRs at week 4. Severe erythema observed at week 2 was significantly associated with lesion clearance compared with mild erythema. At week 4, both severe and moderate erythema, moderate scaling and moderate pruritus were significantly associated with lesion clearance at week 8 compared with mild LSRs. Results according to the LSR severity for patients who had 100% clearance are quite similar.

Conclusion: Our analysis showed that the severity of LSRs during 5-FU 4% treatment for AK was associated with a higher clearance rate. It appears that severe LSRs did not compromise treatment efficacy. Because LSRs can still be unpleasant, strategies must be developed to relieve patients to allow continued 5-FU 4% application.

Keywords: 5-Fluororuacil 4%; Actinic keratosis; Erythema; Local skin reactions; Post hoc analysis.

Plain language summary

Actinic keratosis is a skin disease caused by long-term sun exposure. Damaged skin areas are known as lesions, which may develop into skin cancer if untreated. Topical 5-fluorouracil cream is a treatment for actinic keratosis. Skin reactions such as redness, flaking and itchiness are an expected and short-term side effect of 5-fluorouracil. However, patients may stop treatment if reactions are severe. This study pooled data from two randomised clinical trials of 397 patients with actinic keratosis. The study investigated whether the severity of skin reactions from 5-fluorouracil 4% cream resulted in better lesion clearance 4 weeks after the end of treatment. Patients applied the cream to their lesions once daily for 4 weeks. Four weeks after treatment ended, 81% of patients had at least 75% clearance of their lesions and 19% of patients had less than 75% clearance. Patients who had at least 75% clearance had, before treatment started, more lesions and more severe disease than patients with less than 75% clearance. Patients who experienced the side effect of severe skin redness at week 2 of treatment were likely to have at least 75% clearance of lesions 4 weeks after treatment ended. Also, patients who had side effects at week 4 of treatment that included moderate or severe skin redness and moderate flaky skin or moderate itchiness were likely to have at least 75% lesion clearance 4 weeks after treatment. Results according to the LSR severity for patients who had 100% clearance are quite similar. Importantly, these skin reactions did not negatively affect treatment efficacy.

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Conflict of interest statement

Declarations. Conflict of Interest: Markus V. Heppt has received honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Immuncore, Pierre Fabre and InfectoPharm. Kilian Trin, and Alain Delarue worked in Pierre Fabre Laboratories at the time of the study. Mélanie Groc and Nathalie Bégeault are employees of Pierre Fabre. Anne-Cécile Mille is an employee of Atlanstat. Ethical Approval: This pooled analysis was based on previously conducted studies and does not contain any direct investigation with human participants or animals performed by any of the authors. Studies HD-FUP3B-048 and HD-FUP3B-049 received ethical approval from the institutional review boards of all relevant study sites and were conducted in compliance with US Food and Drug Administration regulations, the ethical principles of the Declaration of Helsinki, and the current International Conference on Harmonisation Good Clinical Practice guidelines. Patients provided written informed consent to participate in the studies.

Figures

Fig. 1
Fig. 1
Forest plot of adjusted odds ratios estimates of the association between LSRs at week 2 and CC/PC at week 8. CC clearance of all lesions, CC/PC clearance of ≥ 75% of lesions, NC clearance of < 75% of lesions, CC complete clearance, CI confidence interval, LSR local skin reaction, NC no clearance, OR odds ratio, PC partial clearance, W week
Fig. 2
Fig. 2
Forest plot of adjusted odds ratios estimates of the association between LSRs at week 4 and CC/PC at week 8. CC clearance of all lesions, CC/PC clearance of ≥ 75% of lesions, NC clearance of < 75% of lesions, CC complete clearance, CI confidence interval, LSR local skin reaction, NC no clearance, OR odds ratio, PC partial clearance, W week
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