Field-targeted therapies more effective

At this year’s AAD, experts presented on the current evidence regarding therapy and prevention. Promising treatment approaches were presented and the importance of sun protection was reinforced.

Squamous cell carcinoma is the second most common white skin cancer after basal cell carcinoma. In Europe, the annual incidence is 30 cases per 100,000 persons with an increase of 50-200% in the last 30 years [1,2]. Actinic keratosis (visible lesions) and oncogenic mutations (invisible precursors) represent common precancerous changes [3]. In the case of chronically sun-exposed skin, there is an increased risk of developing squamous cell carcinoma [4]. Actinic keratosis and squamous cell carcinoma are characterized by atypical proliferation of invasive squamous cells, which can potentially metastasize [5]. Genetic predisposition plays a crucial role in that UV radiation can lead to mutation of the TP53 gene and weakening of antitumor immunity. The tumor suppressor gene TP53 encodes the protein p53, which is a cell cycle regulator that prevents tumor cell transformation. It is one of the main genes involved in blocking the development of malignant tumors [6].

AKASI: Score for quantitative area evaluation

The Actinic Keratosis Area and Severity Index (AKASI) is a standardized measurement tool introduced in 2017 (Fig.1). It is a score for quantitative area assessment of actinic keratosis in the head and face area, which was derived from the scheme PASI (Psoriasis Area Severity Index Psoriasis Area Severity Index) used in psoriasis and is structured similarly (division of the head into four regions; assessment of severity rating based on of three items) [7]. The AKASI can be used for risk stratification, personalization of treatment, follow-up and therapy evaluation.

Therapy studies: Evidence situation

Exclusively lesion-directed therapy is not effective with respect to invisible precursor mutations (TP53 clones) in high-risk patients said Assistant Professor Sean Christensen, MD/PhD, Yale School of Medicine, at the 2019 AAD Annual Meeting [3].

The International League of Dermatological Societies (ILDS) guidelines strongly recommend the following field-directed therapies for multiple actinic keratoses and “field cancerization”: 0.5% 5 FU, 3.75% imiquimod, and 0.015/0%/0,05% ingenol mebutate, and ALA-/MAL-PDT [8]. A weak recommendation was made for cryotherapy, the combination preparation of diclofenac and hyaluronic acid; 5% 5 FU; 0.5% 5 FU+10% salicylic acid; 2.5% and 5% imiquimod, and Er:YAG and CO2 laser treatment [8].

A randomized trial published in 2019 that enrolled 624 patients with at least 5 lesions on the head or neck (Olsen grade 1) compared four treatment modalities. The primary endpoint was healing of at least 75% of lesions after 12 months. The following are the four procedures in descending order of the proportion of patients who met the primary endpoint [9]: Fluorouracil: 74.7% (95% CI; 66.8-81.0%); imiquimod: 53.9% (95% CI; 45.4-61.6%); photodynamic therapy: 37.7% (95% CI; 30.0-45.3%); ingenol mebutate: 28.9% (95% CI; 21.8-36.3%).

According to data published in 2018, positive effects of topical field-directed therapy were confirmed: 954 intermediate-risk patients were randomly assigned to the treatment arm with 5-FU 5% cream twice daily vs. placebo. The treatment period was 2-4 weeks (face and ears). 1 Year after baseline, squamous cell carcinoma was reduced by 75% (1% of patients in the 5-FU group vs. 4% in the control group; p<0,01) [11].
According to a 2018 cohort study in a “real-world” setting, the efficacy of topically applied fluorouracil vs. topically applied imiquimod was compared in individuals with actinic keratosis. Fluorouracil was shown to be superior to imiquimod in reducing the incidence of actinic keratosis two years after baseline [10].

Off-label uses currently include external retinoids such as adapalene or tazarotene and topical colchicine. Topical colchicine has been shown to reduce skin field cancerization [12].

New treatment approaches

Cunningham et al. investigated the efficacy of calcipotriol on a sample of 132 low-risk patients with facial actinic keratosis (2× daily treatment for 4 days) [13]. Subjects were randomly assigned to the 5-FU+calcipotriol condition or the 5-FU+placebo condition. 8 weeks after baseline, the 5-FU+Calcipotriol condition showed 88% reduction in actinic keratosis vs. 26% in the 5-FU+placebo treatment arm. [13]. Calcipotriol is a topical vitamin D derivative used as an immunomodulatory treatment in psoriasis. Comparisons with standard field therapy are pending at this time.

Currently, two randomized-controlled phase III studies (KX01-AK-003, KX01-AK-004) are of interest [14]: According to corresponding phase II studies, the topical SRC kinase inhibitor KX2-391 (ointment 1% with a new dual SRC/tubulin inhibitor as active ingredient) is effective in reducing actinic keratosis. Previous findings suggest that SRC kinase signaling cascades are dysregulated in actinic keratosis and squamous cell carcinoma. SRC kinases are a family of cytoplasmic 60-kD tyrosine kinases (SH2- and SH-3-domain-containing protein tyrosine kinases).

Risk factor sun exposure

That UV radiation and sunlight are the greatest risk factors for non-melanocytic cutaneous tumors has been empirically demonstrated [15]. Prof. Sean Christensen, MD/PhD, pointed out at this year’s AAD Annual Meeting that sun protection could reduce the risk of squamous cell carcinoma by about 40% [3]. According to AAD recommendations, the following criteria should be considered in a sunscreen product: UVA and UVB filters, water resistance, and at least protection factor 30 (SPF) (blocks 97% of UVB rays from sunlight) [16]. Furthermore, WHO points out that sunscreen should be used during outdoor activity even in cloudy weather, as 80% of harmful UV rays can penetrate the skin even under these conditions
[17].

Source: AAD Annual Meeting 2019, Washington (USA)

Literature:

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