Severity of Local Skin Reactions with 4% 5-Fluorouracil Plus Emollient versus 4% 5-Fluorouracil Alone in Patients with Actinic Keratosis: A Single-Blind Randomised Trial

Actinic keratoses (AKs) are cutaneous lesions resulting from cumulative sun exposure that are characterised by proliferation of atypical epidermal keratinocytes [1, 2]. They typically present as multiple lesions in the form of scaly patches, macules or papules with poorly defined borders, and occasionally appear as thick, adherent scales over an erythematous base [3, 4]. AKs can persist in the same stage or may regress spontaneously (15–63% of lesions per year) or undergo malignant transformation into invasive squamous cell carcinoma (iSCC; 0.1–20% of lesions or up to 0.5% of lesions per year) [1, 5]. The prevalence of AK is 11–25% worldwide [6], and depends on the geographical variability in ultraviolet radiation levels [7]. The highest prevalence of AK is in Australia (40–59%) [8, 9], while the prevalence is generally lower across Europe, affecting 4.7% of individuals in France [10], 11.2–23.0% in the UK [11, 12], 27.4% in Italy [13], 28.6% in Spain [14], 31.0% in Austria [15] and 37.5% in the Netherlands [7].

In patients with AK, the primary treatment goals are the eradication (complete or partial) of lesions, improvement in skin appearance, reduction in pain and other symptoms, increase in disease-free intervals and decrease in the overall risk of malignant progression to iSCC [1, 5]. The choice of treatment is based on the location of the lesions and treatment-related factors, as well as patient characteristics and preferences [1, 2]. Lesion-directed treatment may be used in patients with localised or hyperkeratotic AK lesions, and include cryotherapy, laser treatment or surgery (excision, curettage). Field-directed treatments, such as topical treatments [e.g. 5- fluorouracil (5-FU) in concentrations ranging from 0.5% to 5%, imiquimod (3.75% or 5%), diclofenac sodium (3%), tirbanibulin (1%), 5-aminolevulinic acid and methyl aminolevulinate] with photodynamic therapy (PDT) or daylight, are indicated to treat patients with multiple clinical lesions and underlying field damage [1, 2].

Among the available topical options used for field-directed treatment of AKs, 5-FU-containing treatments are effective and widely prescribed [16‐19]. However, as with most efficient topical treatments for AK, 5-FU-containing treatments frequently lead to transient application site reactions, commonly known as local skin reactions (LSRs) [20], which are considered a normal positive response that is related to the pharmacological action of 5-FU [21].

LSRs may manifest clinically as erythema, scaling/dryness, flaking, oedema, crusting/scabbing, erosions/ulcerations, stinging/burning and pruritus, usually peaking after 4 weeks of treatment and resolving within 2–4 weeks of treatment discontinuation [20, 22, 23]. The most recently developed topical 5-FU preparation (Tolak; Pierre Fabre) is composed of 4% 5-FU in an aqueous cream base that contains peanut oil. In clinical trials of this 4% 5-FU preparation applied once daily (one phase II and one phase III trial), the incidence of LSRs was 62–99% by individual symptoms [20, 22]. LSRs were mild to moderate in 17–44% of patients and severe in 6–38% of patients [20].

Even if severe LSRs are less frequent with 4% 5-FU once daily than with 5% 5-FU twice daily [21], the challenge with topical 5-FU treatment remains to reduce the incidence and/or severity of LSRs and improve local tolerance without interfering with its efficacy. One potential tool for overcoming this challenge is the addition of an emollient during 5-FU treatment. The aim of the current study was to investigate whether treatment with 4% 5-FU (Tolak) plus emollient cream (Glycerol Vaseline Paraffin, Pierre Fabre, France) would reduce the severity of LSRs over 4 weeks compared with 4% 5-FU alone in patients with AK.

This phase IV clinical trial in adults with AK lesions showed that the local tolerability and effectiveness of 4% 5-FU were similar with and without the addition of an emollient. The study did not meet its primary objective, as the mean LSR total scores at week 4 showed no statistically significant differences between patients who received 4% 5-FU plus emollient and patients who received 4% 5-FU alone. The proportion of patients with a severe LSR at week 4 was non-significantly lower in the intervention versus the control group for flaking/scaling (10.2% versus 17.2%) and crusting (15.3% versus 22.4%), while there were no between-group differences for the incidence of severe erythema, swelling, vesiculation/pustulation and erosion/ulceration reactions. Although the addition of an emollient did not significantly reduce LSR severity compared with 5-FU alone, the LSR total score in the intervention arm (mean score of 7.1) was at the expected level to show a difference with the control arm (i.e. 7.0), while the LSR total score in the control arm (mean score of 7.7) was better than the expected score (i.e. 10). The latter score was estimated using raw data of the signs of local tolerance from a previous clinical trial of topical 4% 5-FU [23]. Of note, skin reactions led to treatment discontinuation in only 9.9% of patients in the control arm.

The 4% 5-FU formulation contains highly purified peanut oil, which has effective moisturising properties and is safe for use even in patients with peanut allergy [23]. This moisturising property of peanut oil in this 4% 5-FU formulation could be one of the reasons why our study observed no differences in the individual LSR items (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) between the intervention and control groups. However, a trend was observed for crusting and flashing/scaling, indicating that the addition of a second emollient could provide additional benefit for these symptoms.

The severity of LSRs has previously been related to the number of AK lesions at baseline (described below) [21]; therefore, the lower than expected LSR total score in the control arm of this study may be explained by the lower mean number of AK lesions at baseline (12.2 lesions per patient) compared with the previous clinical trials of topical 5-FU (15 lesions per patient) [23].

When LSR total scores at week 4 were compared in the subgroup analysis according to the number of lesions at baseline (< 10 and ≥ 10) or age (< 80 and ≥ 80 years), no statistically significant differences were observed between the intervention and control groups. However, in patients with < 10 lesions at baseline, the LSM between-group difference of −1.51 (95% CI −3.51, +0.49) indicated a possibly clinically relevant effect of the emollient in these patients with less damaged skin. Similarly, patients aged ≥ 80 years had an LSM between-group difference of −2.47 (95% CI −5.47, +0.53), which suggests a clinically relevant favourable effect of the emollient in older patients, who often have very dry skin [25]. Further studies in larger patient populations are needed to verify the potential clinical benefits of adding emollient to 4% 5-FU in older patients or in those with < 10 AK lesions at treatment initiation.

As expected, skin reactions were the most common TEAEs in both the groups; however, there were no new safety signals with the addition of an emollient to the 4% 5-FU treatment regimen.

The rates of complete and partial AK lesion clearance were similar between the treatment groups, confirming that the additional use of an emollient did not compromise the effectiveness of topical 4% 5-FU cream. At week 8, the mean relative reduction in total number of AK lesions versus baseline was −72% in both groups, which is in line with the findings of previous clinical studies of 4% 5-FU (−80%) [23].

The limitations of our study include its single-blind study design, although given the nature of the treatments and their application, a double-blind study design was not feasible. However, all efforts were made to maintain the investigator blinding throughout the study.

The local tolerability of 4% 5-FU remained at an acceptable level, with better LSR total scores than expected. The safety and effectiveness of 4% 5-FU topical cream for the treatment of adults with AK lesions were not significantly modified by the addition of an emollient to the treatment regimen. The emollient may be beneficial in patients with < 10 lesions at baseline or in older patients and may provide slight reductions in severe flaking/scaling and crusting LSRs.