Clinical Management Recommendations The Importance of Medication Adherence in the Treatment of Actinic Keratosis: An Expert Consensus Panel

Background: Actinic keratosis (AK) is one of the most common dermatologic diagnoses. While there are several treatment options, many topical therapies have poor adherence due to duration of treatment and local skin reactions (LSRs). Objective: To review the available literature on the most commonly used patient-administered field-directed therapies for AK and create consensus statements on the role of medication adherence in improving AK outcomes. Methods: A literature search of PubMed was completed for English-language original research articles reporting efficacy, safety, and tolerability data for 5-FU, diclofenac gel, imiquimod cream, and tirbanibulin. Once the articles were selected, they were distributed to a panel consisting of seven dermatologists with extensive expertise in managing AKs. Each panelist reviewed the articles and assigned them a level of evidence based on Strength of Recommendation Taxonomy (SORT) criteria. The panelists then met to review and discuss the studies and created consensus statements on the management of AKs and the importance of medication compliance. A modified Delphi process was used to approve the adoption of each statement. Results: The literature search produced 1,326 articles that met search criteria. After screening these articles for relevance

Actinic Keratosis (AK) is one of the most common diagnoses in the outpatient setting, with an estimated prevalence of 40 million in the United States (US) in 2004 and a rising incidence. 1,2AKs are associated with chronic ultraviolet (UV) damage, and therefore their incidence increases substantially with age. 3 In fact, in the US it is the most common dermatologic diagnosis in patients over 45 years of age. 4,50][11][12][13] The risk of transformation into invasive SCC is difficult to accurately assess, but some studies cite a risk as high as 16% per lesion-year. 14,15ere are two types of treatment methods for AKslesion-directed therapy and field therapy.Lesion-directed therapy targets specific AKs that the clinician is able to identify and is commonly used when there are only a few lesions or for patients who may not be compliant with at-home regimens. 16his includes cryosurgery, laser therapy, curettage, and surgery such as an excision or shave biopsy. 16r patients that present to the dermatology office with numerous AKs, lesion-directed therapy can be cumbersome and inefficient.Additionally, chronic UV exposure can lead to field cancerization, in which areas of cutaneous tissue have a high burden of both clinical and subclinical actinic damage. 5herefore, in order to mitigate the risk of malignant transformation, it is often important to treat the broader area of skin that may include normal appearing tissue with pathologic atypia. 5Commonly used fielddirected therapies include 5-fluorouracil (5-FU), diclofenac, imiquimod, photodynamic therapy (PDT), and tirbanibulin.[18] Tirbanibulin is the newest field-directed treatment and was approved by the Food and Drug Administration (FDA) for the treatment of AKs on the face and scalp at the end of 2020 after two phase 3 clinical trials demonstrated its safety and efficacy. 19One benefit of tirbanibulin is that it has a 5-day course, much shorter than other therapies that require treatment for 2-4 weeks.Early data has also shown that tirbanibulin is very tolerable with minimal LSRs.The purpose of this study was for a panel of experts in AK management to review the available literature on the most commonly used patient-administered field-directed therapies for AK and create consensus statements on the role of medication adherence in improving AK outcomes.

METHODS
with expertise in managing AKs.Each panelist reviewed the articles and assigned them a level of evidence based on Strength of Recommendation Taxonomy (SORT) criteria. 20The panelists then convened on February 16, 2023, to review and discuss the studies and develop consensus statements on the management of AKs and the importance of medication compliance.A modified Delphi process was used to approve the adoption of each statement. 21This process requires a supermajority vote to adopt a statement or recommendation through multiple rounds of real-time voting.Each panel voted a score of 1-9 for adoption.Only statements for which at least two-thirds of the panel voted a 7 or higher were adopted.

Study Selection and Levels of Evidence
The initial literature search produced 1,326 articles that met search criteria.After screening these articles for relevance and applying the inclusion criteria, 17 articles were chosen to be reviewed by the panel and assigned a level of evidence.Of the 17 selected articles, the panel assigned level 1 evidence to nine articles 19,[22][23][24][25][26][27][28][29] , level 2 evidence to three articles [30][31][32] , and level 3 evidence to five articles [33][34][35][36][37] as shown in Table 1 and 2.

Consensus Statements
The panel created seven consensus statements related to AK management.For six of these statements, the panel unanimously voted a level 9 for adoption.There was one statement which was not adopted, as five members of the panel assigned it a level 2 and two members assigned it a level 3 (Table 3).

Statement 1: AK is a common dermatologic disease.
AK is one of the most common dermatologic diseases and is the most common dermatologic diagnosis in adults older than 45 years of age. 4 Its incidence is on the rise, as the number of treated AKs per 1,000 Medicare patients rose 14.6% between 2007 and 2015. 38It is extremely common outside of the US as well, especially in areas that receive significant UV exposure.In Australia, it is estimated that 40% of the population over the age of 40 has at least one AK. 39The World Health Organization calculated that there were 131,433,084 cases of AK across Europe in 2006. 40

Statement 2: AKs can progress to invasive squamous cell carcinoma.
The natural history of AKs and their ability to transform into invasive SCC has been described throughout the literature.One study found that patients with at least 20 AKs had an 11-fold greater risk of developing SCC and 10-fold greater risk of developing basal cell carcinoma (BCC) compared to those without any. 41Not every AK will progress to SCC; in fact, spontaneous regression may occur in 15 to 63% of lesions. 42However, even though some AKs will regress, they often reappear, and new ones develop in areas of chronically sunexposed skin.One survey study of 1,040 people in Australia found 1,873 AKs in 59% of the people screened. 43At 12-month followup, although 26% of the lesions were absent in the subgroup with at least one AK, 60% of these participants developed new lesions. 43verall, the total number of AKs in the studied population increased by 22% at 12 months. 43While it is difficult to predict which AKs will transform into SCC and the individual risk of malignant transformation for each lesion, it is clear that AKs have the

Statement Vote
Statements that were adopted AK is a common dermatologic disease.7 voted 9 AKs can progress to squamous cell carcinoma.7 voted 9 Higher complexity, longer duration, and adverse effects negatively impact adherence to AK treatments.7 voted 9 Lower adherence to AK treatments can lead to lower efficacy.7 voted 9 Prospective, real-world data demonstrate that topical tirbanibulin for AK is effective, well-tolerated, and convenient, based on highly concordant assessments by both patients and clinicians.

voted 9
Payors and other stakeholders are encouraged to reduce barriers to effective, tolerable, and convenient treatments for AKs.7 voted 9

Statements that were not adopted
There is an unmet need for effective AK treatments that are of short duration with limited and tolerable adverse effects.
It is well documented that adherence to topical medications can be very poor for a variety of dermatologic conditions. 49This may stem from a multitude of factors and several studies have attempted to identify these factors and possible interventions.One systematic review of the associations between dose regimens and medication compliance found that compliance decreased as the number of daily doses increased. 50For AK management specifically, literature reporting adherence and persistence for topical treatments is limited, but one study of 224 AK patients on imiquimod (3.75% and 5%), 5-FU 5%, or 5-FU/salicylic acid (0.5%/10%) in Germany, France, and the UK found between 10 and 25% of patients were non-adherent with their prescribed regimen and 23% were non-persistent. 51Another study of 305 AK patients that were either currently using a topical AK therapy (diclofenac sodium 3%, imiquimod 5%, 5-FU 5% or 5-FU/salicylic acid (0.5%/10%)) or had done so within the past 12 months found that 88% of patients were either non-adherent, non-persistent, or both with their regimens. 52nger duration and adverse effects certainly play a significant role in adherence to AK treatments.One study of adherence in 20 patients treated with 5-FU 0.5% reported an average adherence rate of 92% in the first week of treatment, but this fell to 82% by the end of treatment at the fourth of week. 53ommon adverse effects of topical AK therapies such as 5-FU 5% cream, diclofenac 3% gel, and imiquimod 3.75% cream include LSRs such as pain, erythema, burning, stinging, crusting, and flaking. 34,54These adverse effects accompanied with longer regimens between 2 and 16 weeks can require treatment breaks and early cessation. 54In their literature review, Lebwohl et.al found that the most important contributors to non-adherence were lengthy treatment duration, severity and persistence of LSRs, and confusion over treatment regimens. 54atement 4: Lower adherence to AK treatments can lead to lower efficacy.
Lower adherence to treatments has an important negative impact as it can lead to decreased efficacy.This, in turn, results in negative health outcomes such as disease worsening and even death. 55The problem is so significant that the World Health Organization even declared that nonadherence to medications is a "worldwide problem of striking magnitude" in 2003. 56ncomplete treatment of AKs can increase the risk of malignant transformation to SCC, thus leading to increased morbidity and mortality. 14atement 5: Prospective, real-world data demonstrate that topical tirbanibulin for AK is effective, well-tolerated, and convenient, based on highly concordant assessments by both patients and clinicians and this suggests that its usage in AK management could lead to improved adherence.
The Patient Reported Outcomes in Actinic Keratosis (PROAK) study is a real-world, single-arm, prospective cohort study for adult patients with AKs on the face or scalp who were newly initiated with once daily tirbanibulin. 57A total of 300 patients were enrolled from 32 community practices across the US.Ten patients were not included in the 8-week analyses due to missing data, loss to follow-up, or voluntary patient withdrawal of consent.Of the remaining 290 patients, 100% of them completed their 5-day oncedaily treatment course.Importantly, there were no discontinuations due to adverse drug reactions and there were no serious adverse drug reactions reported at 8 weeks. 57Not only was tirbanibulin found to be welltolerated, but it was efficacious as well, with 73.79% of clinicians reporting that their patients AKs were completely or partially (at least 75%) cleared based on investigator global assessment (IGA) at 8 weeks. 58 clinical practice, many patients become frustrated with LSRs from topical therapies and after just one treatment course they are very reluctant to use them again.However, in the PROAK study, for 85.17% of tirbanibulintreated patients, their clinicians reported that they are somewhat or very likely to consider tirbanibulin treatment again if the need arises.Concordantly, 80.0% of patients noted that they were somewhat or very likely to consider tirbanibulin treatment again if the need arises. 57,58These findings suggest that tirbanibulin usage for AK therapy could lead to enhanced therapeutic adherence.While efficacy and tolerability are very important factors to ensure medication adoption and treatment success, accessibility is just as important.Access to tirbanibulin can be limited, as the cost for a 5-day supply of the ointment can be $1,136 for cash-paying patients or those with inadequate insurance coverage. 59One study that compared costs of various field therapies for AK found the per-regimen cost of tirbanibulin was $990. 60his is less expensive than the most expensive medication studied, 5-FU 0.5% cream ($1,332.08),but far more expensive than the least expensive treatment, 5-FU 5% cream ($384.94). 60When patients face choices between AK therapies with long durations and significant LSRs or high costs, they may be discouraged from seeking care.This can subsequently increase the morbidity, mortality, and overall use of healthcare resources from AKs and their associated SCCs.In 2013, the estimated cost of treating AKs in the US was $1.68 billion. 61Early detection and treatment of AKs is imperative for both improving outcomes and decreasing costs to the healthcare system, as one Veterans Affairs study found 3-year savings of $771 per patient treated with 5-FU versus placebo. 62Therefore, improving access to effective, tolerable, and convenient treatments such as tirbanibulin should be a priority for payors.
While there are multiple options for the treatment of AK, there is little consensus on a standard of care.Clearance rates for the most common topical field therapies vary significantly but are also difficult to directly compare due to differences in methodology for measuring and assessing outcomes.After a thorough review of the literature, this panel of dermatologists with significant expertise in managing AKs created six consensus statements related to the importance of AK treatment to prevent the development of SCC and the role that medication adherence plays CONCLUSION in treatment success.Study limitations include that not all therapeutic options for AK were considered and the topical field therapies that were included in the review have not all been compared head-to-head.Overall, it is evident that an efficacious, tolerable, and convenient treatment for AKs is critical to their adequate management and that tirbanibulin may be the best current option to achieve these criteria.

Statement 6 :
Payors and other stakeholders are encouraged to reduce barriers to effective, tolerable, and convenient treatments for AKs.

Table 1 .
SORT criteria level of evidence for each of the articles pertaining to tirbanibulin.

Table 2 .
SORT criteria level of evidence for the articles not pertaining to tirbanibulin.