Dear Editor,
We read with great interest the European consensus‐based guideline by Kandolf et al. for diagnosis, treatment and prevention of actinic keratoses. 1
The guideline confirms that topical agents containing 5‐fluorouracil (5‐FU) are the most effective for clearance of single and multiple actinic keratosis (AK) with field cancerization. In addition, 5‐FU is currently the only topical agent for AK with reported 4‐year follow‐up data regarding a preventive effect of invasive squamous cell carcinoma (SCC). Thus, emphasizing that the main rationale for treating AK is to prevent them from progressing into SCC, the guideline recommends the usage of all available topical 5‐FU‐containing agents with the highest possible grade of recommendation. The tolerability of these agents differs markedly depending on 5‐FU concentration, duration of application, intensity of actinic dysplasia and formulation. Local skin irritation is almost mandatory and inherent to the mechanism of action of 5‐FU. 2 To this end, a new formulation of 4% 5‐FU in aqueous cream once daily was compared with twice daily treatment with 5% 5‐FU in a double‐blind multicentre study involving 841 subjects. This trial revealed similar efficacy, but better tolerability of the 4% formulation (30% vs. 60% application site skin reaction). 3
Nevertheless, 4% 5‐FU may induce local skin reactions (LSRs) that result in premature treatment discontinuation. They typically include facial erythema, irritation and pain. The management of LSRs is therefore central in the AK treatment with 5‐FU. The number of AK lesions at baseline may predict the intensity of LSRs. 4 Severe LSRs unbearable by patients can be managed by reducing the treatment duration as suggested in the 4% 5‐FU labelling with a treatment duration of ‘4 weeks as tolerated’. It was previously reported that 60% of the patients in the 2‐week treatment group demonstrated complete clearance (100% of lesions cleared) and 85% of patients demonstrated partial clearance (75% of lesions cleared). 3 , 5 However, safety results at 2‐week treatment have never been published and we suggest presenting them here to better characterize the safety profile of 4% 5‐FU as one of the highly recommended interventions of the published guideline.
Patients were treated for 5–20 lesions located on face, and/or ears and/or scalp. Severe erythema reduced from 15% to 5%, while mild and moderate erythema increased from 55% and 30%–60% and 35%, respectively, when the treatment duration was reduced from 4 weeks to 2 weeks. Severe irritation disappeared (0%) in the 2‐week treatment group but remained mild and moderate (20% and 25%, respectively) versus 5%, 10% and 15%, respectively, in the 4‐week treatment group.
Pain was mild and moderate (15% and 15%, respectively) in the 4‐week treatment group versus 10% and 0% in the 2‐week treatment group (Table 1). Remarkably, there was no premature discontinuation in the 2‐week treatment group due to local skin reactions, while 15% of patients 4‐week treatment group discontinued prematurely. 4
TABLE 1.
Summary of AK clearance rates and local skin reactions by severity in once daily 4‐week and 2‐week 4% 5‐FU groups (intent‐to‐treat subjects).
| AK clearance rates | ||
|---|---|---|
| Once daily 4‐week 4% 5‐FU (N = 20) | Once daily 2‐week 4% 5‐FU (N = 20) | |
| Complete clearance (100% lesions cleared) | 80% | 60% |
| Partial clearance (75% lesions cleared) | 100% | 85% |
| Severity of local skin reactions | ||||||
|---|---|---|---|---|---|---|
| Local skin reactions from the System Organ Class a | Mild | Moderate | Severe | Mild | Moderate | Severe |
| Erythema | 11 (55%) | 6 (30%) | 3 (15%) | 12 (60%) | 7 (35%) | 1 (5%) |
| Irritation | 2 (10%) | 3 (15%) | 1 (5%) | 4 (20%) | 5 (25%) | 0 (0%) |
| Pain | 3 (15%) | 3 (15%) | 0 (0%) | 2 (10%) | 0 (0%) | 0 (0%) |
| Bleeding | 1 (5%) | 0 (0%) | 0 (0%) | 1 (5%) | 0 (0%) | 0 (0%) |
| Desquamation | 2 (10%) | 2 (10%) | 0 (0%) | 1 (5%) | 2 (10%) | 0 (0%) |
| Dryness | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (10%) | 0 (0%) |
| Pruritus | 2 (10%) | 3 (15%) | 1 (5%) | 2 (10%) | 3 (15%) | 0 (0%) |
| Inflammation | 1 (5%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Oedema | 1 (5%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Swelling | 0 (0%) | 0 (0%) | 1 (5%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Ulceration | 0 (0%) | 1 (5%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Application site reaction | 4 (20%) | 2 (10%) | 3 (15%) | 3 (15%) | 1 (5%) | 0 (0%) |
Counts reflect numbers of subjects reporting one or more local reactions that map to the MedDRA system organ class and preferred term. At each level of summarization (system organ class or preferred term) subjects are only counted once under the greatest reported severity.
Source: KJG\HILL\HDFUDR045\I_AESEV (26 September 2005 11:13).
Globally, the reduction of the treatment duration from 4 to 2 weeks reduced the occurrence of severe LSR from 15% to 5% while maintaining an efficacy benefit (from 80% of complete clearance and 100% of partial clearance to 60% and 85%, respectively). Due to the superior efficacy compared to the 2‐week application regimen, the recommended treatment duration of 4% 5‐FU is still 4 weeks if tolerated. However, these data suggest that the remarkable clearance rate after the 2‐week application of 4% 5‐FU would allow a reduction of the treatment duration when LSRs are unbearable for the patient without risking a sufficient therapeutic outcome. Additional data from observational investigator‐driven studies or expert recommendations for topical 4% 5‐FU interventions are desirable to further support the management of the LSRs.
FUNDING INFORMATION
Funding for this article was provided by Pierre Fabre. The sponsor participated in the conception of the outline; the collection, analysis and interpretation of data; the development of the manuscript; and the decision to submit for publication.
CONFLICT OF INTEREST STATEMENT
MVH received Honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Pierre Fabre and Infectopharm. CU received honoraria from Regeneron, BMS, Beiersdorf, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma and Pierre Fabre.
ETHICAL APPROVAL
HD‐FUDR‐045 (IND #69,841) Independent IRB Inc. 6738 West Sunrise Blvd., Suite 102 Plantation, Florida 33313 954.327.0778; 954.327.5778 Fax; Kim Lerner, Chairperson; Anita McSharry, President; Jessica Leo, Project Leader.
ETHICS STATEMENT
Not applicable.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.