Guidelines for the treatment of AK published in 2016 by Werner et al based on available safety and efficacy data strongly recommend topical agents which combine safety, tolerability, and efficacy. Topical 0.5% 5-FU, 3.75% imiquimod, and 0.015% or 0.05% ingenol mebutate were more strongly recommended compared to topical agents such as diclofenac 3% in 2.5% HA gel, 5% 5-FU, 0.5% 5-FU/10% SA (Actikerall), 5% imiquimod, and 2.5% imiquimod.8 Components of safety used to determine the strength of the recommendations included ‘skin irritation’, ‘withdrawal due to adverse events’, and patient satisfaction with treatment. At the time the Werner et al review was published, clinical trials of tirbanibulin had yet to be conducted; however, this topical agent also combines safety, tolerability, and efficacy like the aforementioned strongly recommended agents. Updated guidelines for the care of AK were published by the American Academy of Dermatology in 2021 and corroborated the recommendations by Werner et al; these guidelines also did not include recommendations regarding tirbanibulin as it had yet to be approved for use by the FDA.40 The data analyzed in this systematic review supports the findings in the Werner et al and AAD guidelines; topical agents with the greatest strength of recommendation balance efficacy with a more acceptable safety and tolerability profile.8,40
A systematic review of patient-reported outcomes (PROs) regarding topical, field-directed therapies for AK published in 2021 (tirbanibulin was not available at the time of review), found that ingenol mebutate was among the most favorably rated treatments.41 Ingenol mebutate was rated higher compared to other topical agents reviewed in the report such as 5-FU, diclofenac sodium, and imiquimod due to its short treatment duration and lack of prolonged LSRs. The authors acknowledge that PROs are an important metric to use when selecting a topical agent for AK, as adherence may be limited by poor tolerability or an inconvenient dosing schedule.41
More favorable safety and tolerability profiles for certain topical agents may also be explained by each agent's mechanism of action. 5-FU metabolites interfere with DNA and RNA synthesis and repair, resulting in DNA strand breaks, alterations in RNA expression, and ultimately cell death.42 5-FU also may increase p53 expression, leading to increased apoptosis in dysplastic cells within the treatment field. Markers of epidermal injury, such as keratin 16, and proinflammatory cytokines, such as interleukin 1B, also are observed to be elevated following topical treatment with 5-FU.42 The resulting necrosis induced by 5-FU may increase local inflammation within the treatment field. Combined with twice daily application for a duration between 2 and 4 weeks, this may result in severe local skin reactions lasting for an extended time period, ultimately proving less tolerable for patients. Alternatively, newer agents, such as tirbanibulin, have mechanisms of action that result in more favorable tolerability profiles. Tirbanibulin inhibits tubulin polymerization and disrupts the proto-oncogene SrC, slowing rapid cell division.38,43 The tubulin-binding exhibited by tirbanibulin was shown to be reversible, with no residual cellular toxicity 5 days after application in vitro.37 Tirbanibulin also increases p53 signaling, arrests cells in the G2-M transition, and induces apoptosis.10,38 As tirbanibulin primarily clears AK lesions through apoptosis, rather than necrosis, inflammation within the treatment field is limited.33 As such, only mild LSRs were observed in phase III clinical trials and treatment-related adverse events, such as pain and pruritus, were limited.10 Combined with a short duration of treatment, tirbanibulin provides an ideal combination of efficacy and tolerability within a topical agent.
Topical agents are important to consider when treating patients who present with multiple AKs; however, adherence to older topical agents may be limited by unfavorable tolerability profiles. Visible skin reactions, especially in the face and scalp prolonged patient discomfort may interfere with daily living activities and social engagements, hence negative impact on quality of life. An ideal topical agent for the treatment of multiple AKs combines efficacy, safety, and tolerability with a short duration of treatment. Clinical trials reviewed in both this systematic review as well as PRO data show that the tolerability of topical agents is strongly associated with adherence to treatment.16,24,41 Newer topicals agents available for use are able to better balance efficacy, safety, and tolerability to improve adherence and, ultimately, better real-world effectiveness.
A systematic review of patient-reported outcomes (PROs) regarding topical, field-directed therapies for AK published in 2021 (tirbanibulin was not available at the time of review), found that ingenol mebutate was among the most favorably rated treatments.41 Ingenol mebutate was rated higher compared to other topical agents reviewed in the report such as 5-FU, diclofenac sodium, and imiquimod due to its short treatment duration and lack of prolonged LSRs. The authors acknowledge that PROs are an important metric to use when selecting a topical agent for AK, as adherence may be limited by poor tolerability or an inconvenient dosing schedule.41
More favorable safety and tolerability profiles for certain topical agents may also be explained by each agent's mechanism of action. 5-FU metabolites interfere with DNA and RNA synthesis and repair, resulting in DNA strand breaks, alterations in RNA expression, and ultimately cell death.42 5-FU also may increase p53 expression, leading to increased apoptosis in dysplastic cells within the treatment field. Markers of epidermal injury, such as keratin 16, and proinflammatory cytokines, such as interleukin 1B, also are observed to be elevated following topical treatment with 5-FU.42 The resulting necrosis induced by 5-FU may increase local inflammation within the treatment field. Combined with twice daily application for a duration between 2 and 4 weeks, this may result in severe local skin reactions lasting for an extended time period, ultimately proving less tolerable for patients. Alternatively, newer agents, such as tirbanibulin, have mechanisms of action that result in more favorable tolerability profiles. Tirbanibulin inhibits tubulin polymerization and disrupts the proto-oncogene SrC, slowing rapid cell division.38,43 The tubulin-binding exhibited by tirbanibulin was shown to be reversible, with no residual cellular toxicity 5 days after application in vitro.37 Tirbanibulin also increases p53 signaling, arrests cells in the G2-M transition, and induces apoptosis.10,38 As tirbanibulin primarily clears AK lesions through apoptosis, rather than necrosis, inflammation within the treatment field is limited.33 As such, only mild LSRs were observed in phase III clinical trials and treatment-related adverse events, such as pain and pruritus, were limited.10 Combined with a short duration of treatment, tirbanibulin provides an ideal combination of efficacy and tolerability within a topical agent.
Topical agents are important to consider when treating patients who present with multiple AKs; however, adherence to older topical agents may be limited by unfavorable tolerability profiles. Visible skin reactions, especially in the face and scalp prolonged patient discomfort may interfere with daily living activities and social engagements, hence negative impact on quality of life. An ideal topical agent for the treatment of multiple AKs combines efficacy, safety, and tolerability with a short duration of treatment. Clinical trials reviewed in both this systematic review as well as PRO data show that the tolerability of topical agents is strongly associated with adherence to treatment.16,24,41 Newer topicals agents available for use are able to better balance efficacy, safety, and tolerability to improve adherence and, ultimately, better real-world effectiveness.
DISCLOSURES
LHK has served either as a consultant, speaker, investigator, or an advisory board member for Almirall, Leo Pharma, and Ortho Dermatologics.
AWA has served as a research investigator and/or scientific advisor to AbbVie, ASLAN, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, Pfizer, and Modmed.
JRR has no conflicts of interest to disclose.
AWA has served as a research investigator and/or scientific advisor to AbbVie, ASLAN, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, Pfizer, and Modmed.
JRR has no conflicts of interest to disclose.
REFERENCES
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2. Leiter U, et al. S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) – short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease. JDDG J Dtsc Dermatol Ges. 18, 400–413 (2020).
3. Ahn CS, et al. The National Ambulatory Medical Care Survey: A resource for understanding the outpatient dermatology treatment. J Dermatol Treat. 25, 453–458 (2014).
4. Bickers DR, et al. The burden of skin diseases: 2004: A joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 55, 490–500 (2006).
2. Leiter U, et al. S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) – short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease. JDDG J Dtsc Dermatol Ges. 18, 400–413 (2020).
3. Ahn CS, et al. The National Ambulatory Medical Care Survey: A resource for understanding the outpatient dermatology treatment. J Dermatol Treat. 25, 453–458 (2014).
4. Bickers DR, et al. The burden of skin diseases: 2004: A joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 55, 490–500 (2006).
