of rapidly proliferating malignant keratinocytes.42 Therapies such as ingenol mebutate that operate via rapid necrosis and significant cytokine release will induce marked brisk erythema, desquamation, crusting, and dermal induration.44 The mechanism of topical 5-Flourouracil(5-FU) as an antimetabolite induces pro-inflammatory cytokines and necrosis in rapidly proliferating epithelium, as seen with the disruption of DNA replication by in S-phase.43,44 These necrosis-inducing agents have demonstrated efficacy in the treatment of AKs and subclinical atypical keratinocytes but can induce brisk LSRs in treated areas potentially negatively impacting long-term adherence.43
Topical agents that induce apoptosis, such as diclofenac which inhibits COX-2 pathways and the keratinocyte-proliferation promoting prostaglandins, can effectively treat AKs while minimizing the intensity and/or duration of LSRs.45-48 Imiquimod is an immune response modifier that, unlike other agents, does not directly impact the epidermis but induces apoptosis by augmenting the inherent immune response and cytokine activity of the host to identify tumor antigens in rapidly proliferating atypical keratinocytes, which can sometimes result in robust LSRs as well as rare visceral symptoms based on interferon induction.49
Tirbanibulin is a new synthetic chemical entity that has shown potent anti-proliferative and anti-tumor activity via several mechanisms, including induction of cell cycle arrest and apoptosis in cancerous cell lines and keratinocytes.50 Its MoA disrupts microtubule formation by binding tubulin and inhibiting polymerization and separately by the disruption of Src kinase signaling, a non-receptor proto-oncogene tyrosine kinase which has been observed in various cancers in vitro.50 One of the advantages of tirbanibulin is that its shorter therapy duration and reduced length and degree of LSRs has the potential to enhance adherence.51
Topical agents that induce apoptosis, such as diclofenac which inhibits COX-2 pathways and the keratinocyte-proliferation promoting prostaglandins, can effectively treat AKs while minimizing the intensity and/or duration of LSRs.45-48 Imiquimod is an immune response modifier that, unlike other agents, does not directly impact the epidermis but induces apoptosis by augmenting the inherent immune response and cytokine activity of the host to identify tumor antigens in rapidly proliferating atypical keratinocytes, which can sometimes result in robust LSRs as well as rare visceral symptoms based on interferon induction.49
Tirbanibulin is a new synthetic chemical entity that has shown potent anti-proliferative and anti-tumor activity via several mechanisms, including induction of cell cycle arrest and apoptosis in cancerous cell lines and keratinocytes.50 Its MoA disrupts microtubule formation by binding tubulin and inhibiting polymerization and separately by the disruption of Src kinase signaling, a non-receptor proto-oncogene tyrosine kinase which has been observed in various cancers in vitro.50 One of the advantages of tirbanibulin is that its shorter therapy duration and reduced length and degree of LSRs has the potential to enhance adherence.51
FUTURE DIRECTIONS
The panel noted inconsistencies in the literature surrounding AKs and recommends additional studies with a special focus on three domains: (1) natural history and clinical presentation of high-risk AKs, (2) efficacy of regimens consisting of a combination of multiple patient-applied therapies, as well as (3) efficacy of patient-applied therapy on non-studied anatomic sites and conditions.
Future studies should endeavor to more clearly elucidate the natural history of AKs. Given an incompletely defined quantitative risk of progression, there is a need for a paradigm to identify those lesions most likely to advance to invasive SCC.
Existing studies demonstrate the additive effects of combining lesion-directed and field therapies28,40 However, there is little data on the efficacy of regimens of patient-applied combination therapies, especially those that function via different MoA. Furthermore, studies examining a role for concurrent topical corticosteroids or other adjunctive therapies to improve adherence by reducing LSRs without loss of efficacy may be reasonable.52
Finally, additional studies further defining the efficacy of patientapplied treatments for actinic cheilitis or other regions of the body (eg, dorsal hands/forearms and chest) could provide more clarity for patient care and further fine-tune individual treatment regimens. Investigations regarding currently off-label uses for these patient-applied agents for other keratinocytic dysplastic processes such as SCC in situ, Bowenoid papulosis, vulvar dysplasias, verruca, and molluscum contagiosum would be helpful.
Future studies should endeavor to more clearly elucidate the natural history of AKs. Given an incompletely defined quantitative risk of progression, there is a need for a paradigm to identify those lesions most likely to advance to invasive SCC.
Existing studies demonstrate the additive effects of combining lesion-directed and field therapies28,40 However, there is little data on the efficacy of regimens of patient-applied combination therapies, especially those that function via different MoA. Furthermore, studies examining a role for concurrent topical corticosteroids or other adjunctive therapies to improve adherence by reducing LSRs without loss of efficacy may be reasonable.52
Finally, additional studies further defining the efficacy of patientapplied treatments for actinic cheilitis or other regions of the body (eg, dorsal hands/forearms and chest) could provide more clarity for patient care and further fine-tune individual treatment regimens. Investigations regarding currently off-label uses for these patient-applied agents for other keratinocytic dysplastic processes such as SCC in situ, Bowenoid papulosis, vulvar dysplasias, verruca, and molluscum contagiosum would be helpful.
CONCLUSION
Integrating data on AK prognosis and management with our
understanding of barriers to treatment is critical to improve
patient outcomes. Further studies are needed to better
understand the clinicopathologic risk factors of high-risk AKs and
how best to integrate and combine new therapies into existing
regimens. Newer therapies with shorter treatment courses and
lesser LSRs may improve adherence and outcomes.
DISCLOSURES
JDR serves as a research investigator, speaker, and consultant for Almirall, Bausch Health (Ortho Dermatology), and Sun Pharma and a consultant for Biofrontera. AWA has served as a research investigator and/or scientific advisor to AbbVie, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, Pfizer, and Modmed. BB serves as an advisory board member and investigator for Biofrontera, SUN (DUSA) Pharma and LEO, Pharma, a speaker for LEO Pharma, and as a consultant for Pierre Fabre, PHD Biosciences and Almirall, Inc. NB has affiliations with Abbvie, Almirall, Biofrontera, BMS, BI, EPI Health, Ferndale, Foamix, Galderma, InCyte, ISDIN, J&J, LaRoche-Posay, Leo, Lilly, Ortho, Pfizer, P&G, Regeneron, Sanofi, SunPharma, Vyne, and Vyome. CC serves as a consultant for Almirall, Inc. GG serves as a consultant for LEO Pharma and Almirall, Inc. and as an investigator for Biofrontera. JSK has served as a research investigator and/or consultant to AbbVie, Boeringer Ingelheim, ChemoCentryx, Incyte, Janssen, Novartis, and UCB, and as a speaker for AbbVie. MGL is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc and is a consultant for Aditum Bio, AnaptysBio, Almirall, Arcutis, Aristea, Arrive technology, Avotres Therapeutics, BioMx, Boehringer-Ingelheim, Bristol- Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy, Evelo, Evommune, Facilitate
