Patient‐reported outcomes of topical therapies in actinic keratosis: A systematic review

Abstract Patients' perspectives on actinic keratosis treatments may have an impact on treatment adherence and, therefore, therapeutic outcomes. We performed a systematic review to assess patients' perspectives of topical, field‐directed treatments for actinic keratoses. A literature search was conducted, and 14 studies were identified encompassing 4433 patients. Only four studies were focused on face and/or scalp, which are the locations that typically impact patients' quality of life. Four studies were clinical trials. One study utilized a validated patient‐reported outcomes (PRO) instrument specifically developed for actinic keratosis. In general, treatment adherence and patient satisfaction were better with shorter‐duration treatment regimens such as ingenol mebutate gel. Imiquimod improved quality of life in one study but not in another. No data was available on topical piroxicam. The findings underscore the need for effective and well‐tolerated, short‐duration topical treatment for actinic keratosis.


| INTRODUCTION
Actinic keratoses (AKs), also known as solar or senile keratoses, are chronic, recurrent cutaneous lesions resulting from the proliferation of atypical epidermal keratinocytes due to prolonged intermittent sun exposure and may progress to cutaneous squamous cell carcinoma. AK is one of the most common reasons for dermatology office visits, especially among the elderly. 1 AK treatments can also be quite distressing to many patients due to impact on daily activities such as work and social engagements, especially for lesions in the face and scalp.
Currently, there are two major categories of AK treatments: Lesion-directed and field-directed therapies. 1 The latter include photodynamic therapy (PDT) and topical treatments such as 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, and piroxicam; they are typically used for treating areas with multiple AKs or clinical evidence of field cancerization. Fluorouracil acts by inhibiting thymidylate synthetase limiting DNA synthesis and causing cell death. [2][3][4] Imiquimod is an immune response modifier which activates Toll-like receptor 7 (TLR-7), causing the release of cytokines by epidermal and dermal dendritic cells; imiquimod also modulates the response of natural killer cells (NKs) and B-lymphocytes. Ingenol mebutate disrupts plasma membranes and mitochondria and induces neutrophil-mediated cellular cytotoxicity. [2][3][4] Both piroxicam and diclofenac inhibit cyclooxygenase enzymes (COX-1 and COX-2). The use of Ingenol mebutate for the field treatment of actinic keratosis has been associated with increased risk of nonmelanoma skin cancer (NMSC) and has been withdrawn from the market.
Understanding patients' perspective regarding topical AK treatments may help optimize patients' adherence and clinical outcomes.  A patient-reported outcome (PRO) is a report coming directly from the patient, concerning her health status and experience with a particular treatment. Patient-reported outcome measures (PROMs) are instruments to assess PROs from a quantitative standpoint. To better understand patients' perspectives of AK treatment, we performed a systematic review of PROs of topical field-directed AK treatment.

| Systematic review development and protocol
The present systematic review was devised based on the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" (PRISMA) guidelines and the Cochrane recommendations for developing a systematic review of patient-reported outcome measure (PROM) studies. The systematic review was further based on a protocol, developed according to the "Preferred Reporting Items for Systematic Reviews and Meta-analyses-Protocol" (PRISMA-P). The protocol has been submitted to the "International Prospective Register of Systematic Reviews" (PROSPERO) for registration and is also available upon request to the Corresponding Author.

| Inclusion and exclusion criteria
Inclusion criteria were the following: P (patients suffering from AK), I (intervention, any topical field treatment for AK), C (all the articles reporting topical therapy for AK, independently from the comparison with another drug or placebo-including imiquimod, ingenol mebutate, diclofenac, piroxicam, 5FU), O (outcomes, PROs/PROMs), and S (study design, any study design).
Expert opinions, comments/commentaries, letters to editor, editorials, case reports, case series, and reviews were excluded.

| Search strategy
Search string consisted of relevant keywords (such as "actinic keratosis" and synonyms-actinic or senile keratosis-and safety, tolerability, quality of life, patient satisfaction, patient-reported outcome-PRO-or patient-reported outcome measure-PROM-patient perspective, patient preference or patient perception), connected by means of appropriate Boolean operators. PubMed/MEDLINE was queried from 1 January 2010 to 6 December 2020, utilizing the "Best Algorithm" option; medical subject headings (MeSH) terms and truncated words/wild-card option were used when appropriate (Table 1).
Extensive cross-referencing and scanning of list of references of each potentially eligible study were performed, in order to minimize the risk of missing relevant investigations. Already available reviews were assessed for ensuring an adequate coverage but were not included in the present systematic review. No time or language filters were applied. The literature search was performed independently by two authors (Nicola Luigi Bragazzi, an expert in research methodology, and Giovanni Damiani, a dermatologist) and disagreements were solved by discussion until consensus was reached.

| Data abstraction
The following data and information were extracted: surname of the first author, study year, country in which the study was performed, sample size, mean age, male percentage, skin phototype percentages, previous history of skin cancer and AK, previous treatment received, PROs/PROMs investigated and major findings and conclusions of the study. Two authors independently (Nicola Luigi Bragazzi and Giovanni Damiani) performed the data abstraction and any disagreement was solved through discussion until consensus was reached. Data abstraction was first pilot-tested in a small sub-set of studies randomly generated from sample of the included studies.
T A B L E 1 Search strategy adopted in present systematic review

Search strategy item Search strategy details
String of keywords ("actinic keratosis" OR "solar keratosis" OR "senile keratosis") AND (safety OR tolerability OR satisfaction OR "quality of life" OR "patient satisfaction" OR "patientreported outcome" OR PRO OR "patientreported outcome measure" OR PROM OR "patient perspective" OR "patient preference" OR "patient perception")

| Literature synthesis
Data extracted was synthesized and displayed using tables, charts, and a narrative overview.

| Literature search
The initial literature search yielded a pool of 594 items ( Figure 1).
After screening title and/or abstract, 579 were removed. Three studies were excluded with reason (Table 2). Finally, 14 studies were included in the present systematic review (Table 3).

| Characteristics of the included studies
Included studies were published between 2010 and 2020. Only four studies were clinical trials. 10
One study used a validated questionnaire, the Morisky Medication Adherence Scale (MMAS), to quantify patients' adherence. 13

| DISCUSSION
Actinic keratoses are chronic, recurring lesions and represent a substantial disease burden due to their high prevalence and associated risk of frank malignancy. Furthermore, AKs are quite distressing to many patients not only as a cosmetic liability, but also treatmentrelated local skin reactions occurring on habitually exposed body loca- Imiquimod showed efficacy 17 but lower tolerability and patient's satisfaction than ingenol mebutate. 8,13,30 Furthermore, imiquimod can trigger latent, unpredictable inflammatory dermatoses, particularly on the scalp 31 and also may trigger distant inflammatory mucosal reactions. 30 In addition to tolerability, prolonged treatment duration is a significant factor contributing to nonadherence and nonpersistence to topical treatments. In a community-based, cross-sectional study, patient-applied topical therapies that required less frequent application and have shorter treatment duration were associated with better adherence rates. 32 Our study results shows that patient satisfaction corresponds with shorter duration of topical treatment.
Involving patients and empowering them, implementing patientcentered care and taking into account patients' preferences and perspectives could enhance and improve their health status, paving the way also for personalized management options. Within this conceptual framework, patient education is fundamental, especially for multiple AK lesions. Pretreatment education is appreciated by patients and results in a high treatment satisfaction scores (in the range 86-89%). 12 New venues in the field could include the study of the feasibility of exploiting educational videos or the new information and communication technologies (ICTs) to improve patients' satisfaction and adherence to the treatment. 14 On the other hand, despite its transparency, rigor, methodological strengths, and reproducibility, the present study is not without limitations. The major shortcomings are given by the small studies included and by mining only PubMed/Central. The high heterogeneity among studies did not enable to carry out a meta-analysis.

| CONCLUSIONS
Actinic keratoses are precursors for invasive cutaneous squamous cell carcinoma. Different treatment options exist for actinic keratoses.
Topical therapies with simpler and shorter-treatment regimen