Expanding treatment armamentarium for actinic keratosis and Bowen’s disease

The treatment arsenal for patients with actinic keratosis and Bowen’s disease has expanded in recent years. Topical 5% 5-fluorouracil remains the first-line therapy for actinic keratosis, although several alternatives are available for those who can not tolerate it. For Bowen’s disease, surgical excision is still the first choice based on its efficacy. However, 5-fluorouracil has shown various benefits compared with the surgical approach.

Actinic keratosis and Bowen’s disease represent 2 forms of intra-epidermal neoplasia, which are precursor conditions to squamous cell carcinoma (SCC). Actinic keratosis is characterised by multiple erythematous keratotic plaques with indistinct borders appearing on areas of sun-damaged skin. Patients may also have subclinical lesions. An erythematous keratotic plaque can also be observed in patients with Bowen’s disease, but here, it has well-demarcated borders, is primarily a solitary lesion, and is not necessarily located in a sun-exposed area. Moreover, these patients often do not have subclinical abnormalities. “Histologically, actinic keratosis is observed only in a part of the epidermis, whereas Bowen’s disease can be seen across the full thickness of the epidermis,” said Dr Klara Mosterd (Maastricht University Medical Center, the Netherlands) [1]. “Notably, histological classification of these lesions does not appear to have prognostic value.” In contrast, the Olsen clinical classification of actinic keratosis does have prognostic value. The classification categorises lesions into 3 grades: minimally palpable and hardly visible (grade 1), palpable and visible (grade 2), and thick and hyperkeratotic (grade 3).

Regarding the available treatments for actinic keratosis, topical 5-fluorouracil has delivered the most favourable outcomes in a randomised-controlled trial, comparing it with imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), and ingenol mebutate gel [2]. In this trial, 625 participants with 5 or more actinic keratosis lesions were included. At 1-year follow-up, a 75% reduction of lesions was achieved in 74.7% of the participants on 5-fluorouracil, compared with 53.9%, 37.7%, and 28.9% of those on the other 3 therapies, respectively (P<0.001 for all). Although the 4-year risk of SCC was numerically lower in participants treated with 5-fluorouracil (2.2%) than in those receiving imiquimod (5.8%), ingenol mebutate (3.0%), or MAL-PDT (3.6%), the differences were not statistically significant [3]. “Importantly, the study was not powered for this outcome measure,” commented Dr Mosterd. The study also reinforced the prognostic value of the Olsen classification by showing an association between the grade of lesions and the risk of SCC. The risk was only 2.7% in participants with grade 1–2 lesions and significantly increased to 33.5% in participants with grade 3 lesions. “Thus, the Olsen system is an easy-to-use clinical biomarker with prognostic value,” said Dr Mosterd.

Another study investigated the chemopreventive effect of a single course of 5-fluorouracil cream on the development of non-melanoma skin cancer in 932 high-risk participants. At 1 year of follow-up, the incidence of SCC was 1% in the active arm and 4% in the placebo arm, confirming a chemopreventive effect of this therapy. However, at 4 years of follow-up, the SCC rates were comparable, being 11% and 12%, respectively, suggesting that the course should be repeated annually to maintain its protective benefit [4].

“Since treatment with 5% 5-fluorouracil can cause side effects that may compromise patient compliance, 4% 5-fluorouracil has been explored as an alternative treatment,” Dr Mosterd continued. One study showed that this formulation is somewhat better tolerated and non-inferior to 5% 5-fluorouracil after 4 weeks of therapy [5]. However, long-term evidence is needed to determine whether 4% 5-fluorouracil is a feasible alternative. Other treatments currently under investigation for patients with actinic keratosis are daylight photodynamic therapy (PDT), diclofenac 3%, tirbanibulin, 0.5% 5-fluorouracil combined with 10% salicylic acid, and 5% 5-fluorouracil combined with 0.005% calcipotriol.

In Bowen’s disease, a randomised study evaluated the efficacy of surgical excision versus 5% 5-fluorouracil and PDT [6]. The trial included 250 participants aged 18 years or older, presenting with Bowen’s disease lesions and suspected SCC. They were allocated to receive either surgical excision with a 5 mm margin, 5% 5-fluorouracil twice daily for 4 weeks, or 2 sessions of PDT. At 1 year of follow-up, sustained clearance rates were 97.4% in the surgery arm, 85.7% in the 5-fluorouracil arm, and 82.1% in the PDT arm. “The rates of the non-invasive therapies fell within the non-inferiority margin of a 20% difference compared with surgical excision,” explained Dr Mosterd. Furthermore, 5-fluorouracil was associated with improved quality-of-life outcomes and a better cost-effectiveness profile than surgery. “Also, the aesthetic results of non-invasive therapies are superior to surgery,” added Dr Mosterd. Finally, she mentioned that recurrences following non-invasive therapies are easily managed, mainly reducing the risk of SCC.

1. Mosterd K. Actinic Keratosis/Bowen’s disease: New therapies/insights. Dermatologendagen 2025, 10–11 April, Apeldoorn, the Netherlands.
2. Jansen MHE, et al. N Engl J Med 2019;380:935-946.
3. Ahmady S, et al. JAMA Dermatol. 2022;158(6):634-640.
4. Weinstock MA, et al. JAMA Dermatol. 2018;154(2):167-174.
5. Dohil MA. J Drugs Dermatol. 2016;15(10):1218-1224.
6. Ahmady S, et al. J Am Acad Dermatol. 2024;90(1):58-65.

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Posted on 5 June 2025