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Management of multiple AKs continues to challenge dermatologists and their patients. Despite the arrival of numerous topical options on the market, a recent global analysis shows that a majority of dermatologists are adopting combination approaches in efforts to maximize efficacy, approaching the entire field of photodamage as well as visible actinic keratoses. Perhaps surprisingly, the same analysis shows that the combination of long-standing interventions cryotherapy and 5-fluorouracil cream (with a success rate of approximately 90 percent, per the analysis) is among the most popular interventions. Despite its age and well-known potential for robust local skin reactions, 5-FU accounted for about 40 percent of the AK treatment market in 2018.1

That same report suggests that the global actinic keratosis treatment industry is estimated to reach $1.56 billion by 2026, growing 4.2 percent from 2019. As the population continues to age, and as we see AKs developing in younger patients, the number of AKs needing to be treated will only increase.

Although there is some discrepancy in the rate of conversion (estimated between 0.025 and 16 percent), there is no doubt that a certain number of AKs will progress to SCC. Risks vary with age, gender, chronic UV exposure, and location of AKs.2,3 Therefore, treatment of AKs—both visible and on the way—remains important.

AK Treatments in Context

Local skin reactions associated with most topical AK treatments have been an historical concern. Many patients have refused treatment outright or postponed treatment due to concerns about treatment-associated erythema, swelling, blistering, and pruritus. The lack of standard protocols for managing local skin reactions may hinder care; it is reasonable to assume that dermatologists could maximize patient adherence with standardized protocols in place.

While dermatologists would prefer to make therapeutic decisions based solely on the presentation plus data on the available treatments, AK remains a diagnosis for which cost considerations often come into play. Patients with high deductible insurance may by choice or necessity delay treatment of these “pre-cancerous” lesions until they meet their deductible. This is increasingly true as younger, pre-Medicare patients (as young as their 30s and 40s) present with AKs. Even among our older Medicare patients, those facing the “donut hole” in their prescription coverage may also delay or refuse treatment.

Further complicating matters, until the approval of tirbanibulin late last year, the market had seen no new agent approved for AKs since 2012. There has been limited industry support for research and education in AK.

The Inflammation Conundrum

As noted, inflammatory responses to topical AK therapy has been an historic concern. In some regards, prescribers may be more focused on these responses than the vast majority of patients truly are. Of course, just one very uncomfortable and unhappy patient can require a significant amount of the physician’s time and attention, and that can lead to skittishness on the part of dermatologists. Proper expectation building, education that local skin reactions are expected/normal, and guidance on palliative interventions can be enough to encourage adherence in many cases.

In general, the effects of topically applied AK therapies are non-systemic, although it should be noted that imiquimod is the only AK drug that induces a systemic immune response, part of which may include flu-like symptoms and myalgias.

One of the primary approaches to managing local skin reactions has been to modify the frequency and/or timing of drug application. Variation in the number and timing of drug applications can lead to increased tolerability and potentially improved adherence. Notably, not all regimens have been studied in a controlled manner, leading to some concerns about overall efficacy. Nonetheless, modified regimens generally are considered effective.

Therapeutic Developments

A somewhat recent development is the combined use of calcipotriol and 5-FU.4 Calcipotriol induces thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine that induces robust antitumor immunity. When compared to bland emollient plus 5-FU, the combination of calcipotriol ointment plus 5-FU was superior. There was a mean 87 percent reduction in AKs with the combination, compared to 26 percent reduction with 5-FU alone. There was a higher incidence of burning and erythema in the combination group (38 percent compared to 13 percent). Further studies are warranted. Ideally, a combination formulation could be developed, although there are potential stability concerns.

New to the market is tirbanibulin 1% ointment (Klisyri, Almirall), a first-in-class topical microtubule inhibitor approved for the treatment of AKs.

Tirbanibulin is a synthetic chemical entity with potent anti-proliferative and antitumoral effects in vitro and in vivo. By binding tubulin and inhibiting its polymerization, tirbanibulin induces cell cycle arrest and ultimately apoptotic cell death. Diclofenac also induces apoptosis, whereas 5-FU and ingenol mebutate induce necrosis, correlating to the anticipated local skin reactions.

Apoptosis does not lead to sustained inflammation, likely because there is a reduction in cytokine release. As a consequence, tirbanibulin has a favorable tolerability profile. While tirbanibulin has not been compared head-to-head with other agents, the rate of local skin reactions that could be dose-limiting appears to be significantly lower, compared to what is typically seen with 5-FU or imiquimod.

Klisyri is approved for once-daily application for five days—a regimen that is expected to lead to high levels of adherence. Patients prefer once daily topical therapy with short duration and lower rate of local skin reactions. Tirbanibulin is intended for field-directed therapy, to be applied to the entire anatomic unit where AKs are found. However, the ointment is provided in five individual sachets. While the individual sachets ensure proper dosing and can be convenient, they may limit the prescriber’s flexibility to modify regimens or cover larger surface areas, which is being further investigated.

A New Option for Chemoprevention

The ability to prevent precancers and cancerous lesions is highly preferred to treating lesions that have developed. A new oral formulation of Polypodium leucotomos Extract (PLE) 240mg and Nicotinamide 500mg (Heliocare Advanced Antioxidant Supplement with Nicotinamide, Ferndale) is now available.

PLE exhibits significant chemopreventive and anti-inflammatory properties against UVB-induced damage and inhibition of reactive oxygen species. It decreases UV mediated cellular apoptosis and necrosis and inhibits abnormal extracellular matrix remodeling. Additionally, it mitigates cellular effects of UV radiation as measured by sun burn cells, CPD dimers, Ki-67, and Cox 2.

Polypodium leucotomos and nicotinamide reduces cellular damage induced by visible and infrared light.

In clinical trials, topical tirbanibulin met the primary endpoint and achieved a significantly higher number of patients with complete (100 percent) clearance of AK lesions at day 57 in the treated area compared to vehicle (44 percent vs. five percent in study 1 and 54 percent vs. 13 percent in study 2; p<0.0001 for both studies). It also met the secondary endpoint of partial (≥75%) clearance of lesions at day 57 compared to vehicle. The most common adverse events were application-site pruritus and pain seen in nine percent and 10 percent of patients treated receiving active treatment. There was no discontinuation of therapy due to tolerability issues.


2. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007 Sep;33(9):1099-101.

3. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42(1 Pt 2):23–4.

4. Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest. 2017 Jan 3;127(1):106-116.

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