A 3.75% cream formulation is also available, which is applied nightly for 2 weeks followed by a 2-week rest period, then followed by another 2-week treatment period. The lower concentration is designed for a shorter treatment duration as well as a larger treatment area (200 cm2 vs 25 cm2 for the 5% cream). However, clinical efficacy may be reduced, with large scale clinical trials only demonstrating a clearance rate of 36%.39
Diclofenac is a nonsteroidal anti-inflammatory drug that inhibits cyclooxygenase-2 (COX-2) and prostaglandin synthesis. The exact mechanism behind AK clearance remains unclear, but it is believed that diclofenac induces anti-inflammatory and anti-angiogenic effects, which may induce anti-proliferative and apoptosis mechanisms.40 Topical diclofenac 3% is available in a gel combination with 2.5% hyaluronan. The gel is applied twice daily for 60–90 days. In a meta-analysis of 3 trials involving 364 patients, treatment with 3% diclofenac in 2.5% hyaluronan gel led to complete clearance in 40% of subjects.41 An advantage of diclofenac treatment is the relatively mild cutaneous effects relative to other therapies such as 5-FU.42
Ingenol mebutate, an extract from the sap of the Euphorbia peplus plant, is a newer addition to the array of AK treatments. The agent operates through a two-fold mechanism that induces both rapid cell necrosis and delayed immunostimulatory effects. Within the first few hours, ingenol mebutate causes cell death through the disruption of the plasma membrane and mitochondrial swelling, a process that is later followed by neutrophil-mediated, antibody-dependent cellular cytotoxicity.43 Due to the rapid effects, ingenol mebutate treatment courses are substantially shorter than other topical agents. A 3-day course of 0.015% gel is used for facial/scalp lesions, and a 2-day course of 0.05% gel is used for trunk/extremity lesions.In a randomized controlled trial of 547 subjects with AKs of the face and/or scalp, ingenol mebutate led to clearance in 42% (vs 3.7% with placebo; P less than .001).44 Of 458 patients with AKs of the trunk and/or extremities, clearance was achieved in 34% (vs 4.7% in placebo; P less than .001). Local skin reactions peaked at day 4 following face/scalp treatment and between days 3 and 8 following trunk/extremity treatment, with reactions decreasing to baseline by day 29.
5-fluorouracil (5-FU) is a pyrimidine analogue that inhibits the enzyme thymidylate synthetase, thereby blocking DNA synthesis.45 This disruption of cell division preferentially affects neoplastic cells, providing for the treatment of AKs.Topical 5-FU is available in a cream formulation at 5%, 1%, or 0.5%, or in a solution formulation at 5% and 2%. The most common treatment regimen is application of the 5% cream twice daily for 2–4 weeks. In a meta-analysis of 5 randomized controlled trials, treatment with 5% 5-FU led to an average clearance rate of 49%.46 As with other field treatments, 5-FU is associated with inflammation, erosion, and ulceration during treatment, which may last 1-2 weeks after the application period has ended.The relative efficacies of different AK therapies were evaluated in a meta-analysis by Gupta et al.47 The following eight agents were examined: 5-ALA PDT, MAL-PDT, cryosurgery, diclofenac in hyaluronan gel, 5-FU, imiquimod, ingenol mebutate, and placebo. Thirty-two trials were included, and agents were graded based on their ability to achieve complete clearance. Results ranked the agents as follows: 5-FU > ALA-PDT ≈ imiquimod ≈ ingenol mebutate ≈ MAL-PDT > cryosurgery> diclofenac in hyaluronan gel > placebo.
Investigational therapies are being studied with the goal of improving drug tolerability and patient compliance. KX2-391 ointment 1% is a novel field treatment currently in clinical trial development. The agent functions as a dual Src tyrosine kinase and tubulin polymerization inhibitor, thereby blocking the growth of human keratinocytes and inducing apoptosis in dividing cells.48 In a phase II open-label study, once-daily application of KX2-391 ointment 1% was examined using either a 3-day or 5-day treatment regimen (n=84 in each cohort).49 At day 57, 43% of subjects in the 5-day cohort achieved complete clearance, compared with 32% in the 3-day cohort. Within the 5-day cohort, 52% of subjects with AKs on the face and 33% of subjects with AKs on the scalp attained clearance. Local skin reactions were mostly mild and transient. Based on these results, phase III placebo-controlled trials using once daily KX2-391 ointment 1% for 5 days are currently underway (ClinicalTrials.gov Identifier: NCT03285477).SR-T100 gel is an anti-proliferative agent derived from the medicinal herb Solanum undatum. The active ingredients, solamargine and solasonine, penetrate the cell membrane through simple diffusion and induce cell death by apoptosis. In a phase III double-blind vehicle-controlled trial, 16-week treatment with once-daily application of SR-T100 gel led to clearance in 32.4% of patients, although these results were not significantly higher than in the placebo group (17.1% clearance; P equals 0.111).50 VDA-1102 ointment is an anti-neoplastic agent containing a voltage-gated anion channel/hexokinase 2 modulator, which prevents glycolysis and triggers apoptosis. A phase 2b trial