Refusal of Retreatment With Topical 5-Fluorouracil Among Patients With Actinic Keratosis: Qualitative Analysis

Background Actinic keratosis (AK) is a common premalignant skin lesion, and topical 5-fluorouracil (5-FU) is commonly used in field-directed therapy. However, 5-FU is associated with frequent local skin reactions. Objective This study aimed to qualitatively assess experiences among patients with AK who refuse retreatment with 5-FU. Methods Semistructured interviews were conducted with 10 adult participants who had received treatment with 5-FU for AK between January 1, 2017, and January 1, 2020, and refused future treatment with 5-FU. Results were analyzed using qualitative research methods. Results Although most participants had low concern upon having received a diagnosis of AK, most felt that treatment is very important. When initiating treatment with 5-FU, most cited recommendation by their health care professionals as the primary motivator and initially had low concern regarding treatment. The side effects associated with treatment were physically and psychosocially burdensome for most participants and led to temporary lifestyle adjustments. After treatment, most did not believe that their health care provider prepared them for treatment or were unsure. While half of the participants felt that 5-FU helped treat AKs, half were either unsure, due to premature discontinuation, or did not think that 5-FU treated their AKs. Conclusions 5-FU is one of the most commonly prescribed treatments for AKs, yet most patients experienced both a physical and psychosocial burden with the treatment. Inability to assess efficacy due to premature discontinuation secondary to 5-FU–related reactions is common, and shared decision-making, navigating treatment options, and taking into account patient preferences may be critical to help assure better adherence and outcomes. Although our study was limited by input from participants who refused future treatment with 5-FU, most stated that they would still continue to seek treatment for AKs in the future and would consider other topical treatments, especially if associated with a milder tolerability profile.


Introduction
Actinic keratosis (AK) is a common premalignant lesion clinically presenting as a scaly, red papule on sun-exposed areas of the skin [1]. AKs are treated using a variety of different treatment modalities to prevent progression to invasive squamous cell carcinoma [2]. Treatments can either be lesion-directed (for limited lesions) or field-directed therapies that target areas of skin with multiple AKs and clinical evidence of field cancerization [2].
Topical 5-fluorouracil (5-FU) is a commonly used field-directed therapy to treat AK [2]. It blocks DNA synthesis by inhibiting thymidylate synthetase, which targets the rapidly growing dysplastic cells involved in AK pathogenesis and causes the cells to undergo apoptosis [3]. Topical 5-FU may also be the most efficacious field-directed treatment for AK according to a network meta-analysis [4]. While topical 5-FU is commonly used to treat AKs, many patients experience adverse effects, especially burdensome local skin reactions (LSRs), including inflammatory erythema, scaling, crusting, swelling, erosion, and localized pain [3,5]. LSRs are seen in up to 90% of patients [5]. These can be bothersome and can interfere with activities of daily living and social engagements, leading to a negative impact on quality of life [6].
Adverse effects, frequent dosing, and prolonged duration of treatment can lead to poor adherence, early discontinuation of treatment, and may deter patients from future retreatment with 5-FU [5]. Few studies have assessed adherence to topical 5-FU, and LSRs may discourage patients from seeking treatment for future AKs; some patients refuse to use 5-FU a second time, potentially increasing the risk of malignant transformation [5,7]. Moreover, there is limited literature assessing patient experience with 5-FU treatment. Previous studies using interventions, such as educational videos, to improve patient satisfaction have also not been successful [8]. To further characterize the adverse effects of topical 5-FU and its impact on future use, we qualitatively assessed patient experience among those who stated they would refuse future treatment with 5-FU.

Recruitment
Participants who received a clinical diagnosis of AK (ICD10: L57) and had received treatment with 5-FU between January 1, 2017, and January 1, 2020, were identified through a retrospective review of patients from the Atrium Health Wake Forest Baptist Dermatology Clinic. Potential participants were contacted for assessment, and telephone interviews were conducted with 10 participants who refused future treatment with 5-FU. Multiple reports analyzing patient cohort sizes in qualitative research have suggested the utility of a small sample size, particularly among homogenous populations, such as ours, to address the research question. Specifically, certain commentators have suggested a sample size of 10 to be adequate to sample among a homogenous population [9,10]. Participant recruitment was additionally terminated once thematic saturation was achieved. Each participant received a unique identification code as "Pt#."

Interviews
Data were collected through audio-recorded semistructured interviews. Interviews lasted between 7 and 33 minutes.
Participants were asked about details regarding 5-FU use (indication, dose, duration, outcome, and condition response), medication regimen details (additional medications taken), impact that treatment has had on patient life, and adverse effects experienced. Every participant was asked 22 core questions (Textbox 1). Additional questions were asked to clarify or expand upon responses.

Method of Analysis
The semistructured participant interviews were recorded, carefully reviewed, and then transcribed verbatim upon conclusion of participant interviews. Results were then analyzed using both descriptive statistics and a qualitative research method. The interview transcriptions were initially reviewed by study team members (RS, SM, and SRF) and then coded by 2 members of the study team (RS and SM). Preliminary codes were initially identified using open coding and collaborative analysis. The codes were then clustered in accordance with categories, and themes were then used for further data refinement per conventional qualitative analysis as described in literature [11]. Representative quotations were extracted for illustrative purposes. NVivo (version 11; QSR International) software was used to analyze data and aid in data management.

Ethical Considerations
This study received ethics approval from the Wake Forest University of Health Science's institutional review board (IRB00077121).

Overview
A total of 1276 potential participants were identified (mean age 68 years, 69% male, and all of them were White). All of the 10 participants included in this study identified as male and were White (mean age 66 years, range 39-89 years). Participant interviews revealed 4 major themes centered on how participants felt and their concerns about a diagnosis of AK, motivation to start 5-FU treatment, experience during treatment and perception of preparation, and how treatment affected perception of AK and future care.

Participants' Concerns and Input When Diagnosed With AK
There was low concern among most participants upon having received a diagnosis of AK, although some were shocked or unhappy with their diagnosis. While most were not overly concerned regarding their diagnosis, almost all participants considered treatment very important, and most specifically cited the underlying carcinogenic etiology of the lesion as the reason for the criticality of treatment. Other less commonly stated reasons for concern included general health concerns and embarrassment associated lesion appearance (Table 1).

Patient Motivation to Start 5-FU Treatment
When participants were asked why they initiated therapy with 5-FU, almost all stated the recommendation by their health care provider (HCP) as the reason. Moreover, almost all participants stated they had no or very low concern at the time 5-FU was recommended and prescribed by their HCP. Trust in the prescribing HCP was a pervasive subtheme that participants mentioned to explain the lack of concern. Most participants had received prior interventions for their AKs, and only 3 participants stated they had never received any previous treatment for AK. Among the treatments referred, cryosurgery and other surgical interventions were the most common. Photodynamic therapy and treatment with another topical medication were also referenced. Only one participant stated having previously discontinued treatment for AK (Table 1).

Experience During Treatment and Perception of Preparation
Almost all participants experienced difficulty during treatment with 5-FU, specifically due to symptoms from 5-FU-related adverse effects. Pain or burning at the site of the application was most commonly reported by participants. Other common adverse effects that caused patient difficulty during treatment included red or inflamed skin, peeling, sloughing, and flaking of the skin, and blistering of the skin at the site of application. Most participants stated that symptom onset occurred within days of 5-FU application and resolved within days to 2 weeks after application cessation. However, there was a particular subset of participants who reported residual effects of the medication for months after application cessation ( Table 2).
Treatment with 5-FU also was associated with a negative impact on participant self-perception. Particularly, many participants stated they felt self-conscious or embarrassed while receiving treatment, particularly in those who experienced visible inflammation in their skin with associated blistering or peeling of the skin at the site of application. The treatment, and associated visible symptoms, also caused a pervasive impairment in the social activities of participants, although most stated that the treatment itself did not physically limit them from completing daily activities. A subset of the participants also experienced impaired sleep during treatment (Table 2).
When asked regarding challenges faced while on treatment, most participants referenced 5-FU-associated pain and an overall lifestyle adjustment they had to make while on therapy. Specifically, participants stated issues with application of the medication, especially around bedtime to avoid smearing of contents, and preparation for their social appearance (Table 2).
Overall, all participants felt they were not adequately prepared by their HCP on what to expect while on treatment and few were also unsure whether their HCP had adequately informed them before treatment. During treatment, participants reported that they either received support from their family and their physician or their staff, from just their family, or just from their physician or staff. Some participants, however, stated that they received no support while on treatment ( Table 2).

How 5-FU Treatment Affected Patient Perception of AK and Future Care
Participants stated having mixed feelings while receiving treatment with 5-FU. While some stated treatment was fine or a minor convenience, other participant responses included feeling self-conscious. Including those who stated that treatment was a minor inconvenience, more participants felt uncomfortable and self-conscious during treatment with 5-FU. Particularly, of the participants who felt uncomfortable and self-conscious, some stated that treatment was very difficult for them (Table  3). There were mixed responses from participants about whether treatment with 5-FU helped treat AK. Half of the participants believed that 5-FU helped treat their AKs, while the other half of the participants were not sure or stated that it did not help. Inability to assess treatment responses due to premature discontinuation of 5-FU was a particular subtheme. Specifically, 4 participants stated that side effects from 5-FU use caused them to stop treatment (Table 3).
Although some participants were satisfied with treating AK owing to its potentially carcinogenic nature, mental health impairment and lifestyle inconvenience were other particular subthemes. There was a pervasive belief among participants that it was either difficult to assess or the benefits of treatment were not worth the side effects associated with 5-FU (Table 3).
Despite all participants stating that they would refuse future treatment with 5-FU for AK, most stated that their experience with 5-FU would not deter them for seeking future alternative treatment, and they would be open to other topical treatments, specifically if associated with fewer side effects (Table 3).

Principal Findings
All patients in our cohort refused future retreatment with 5-FU. Despite an overall low concern when diagnosed with AK, most participants believed that treatment was important. There are multiple treatment options for AKs, including both surgical and field-directed treatments, and cryosurgery and 5-FU are the most commonly prescribed therapies [2,12]. While cryosurgery is intended to treat isolated or a few lesions, topical treatments, such as 5-FU, are more efficacious to treat both clinical and subclinical AKs [2,12,13]. However, 5-FU is associated with frequent LSRs, and patients with a greater number of AKs at baseline may be predisposed to severe LSRs [14,15].
Most participants stated that they had had low concern with therapy before initiating treatment and trusted the recommendation of their HCP. However, after completing treatment, most participants stated that they were either unsure or were not adequately prepared by their HCP. Moreover, there were mixed responses regarding the efficacy of 5-FU treatment. Specifically, many participants did not believe that treatment helped their AKs. Inability to assess effectiveness due to premature discontinuation secondary to 5-FU-related adverse events (AEs) was also a common theme. There was a pervasive theme that the side effects associated with treatment were not worth the benefits.
Altogether, participants experienced both physical and psychosocial burden secondary to topical 5-FU treatment. During treatment, 5-FU-associated pain or burning, erythema, peeling, sloughing, and flaking caused difficulty to participants. Particularly, 5-FU-associated reactions had a negative impact on participant self-perception and caused feelings of self-consciousness and embarrassment. Social impairment during treatment, secondary to 5-FU-associated LSRs, was another common theme. Although treatment did not prevent participants' abilities to complete daily activities, it led to lifestyle changes and limitations. Sleep impairment and prevention of 5-FU smearing onto bedsheets was a notable subtheme.

Limitations
Our study was limited by input from participants who refused future retreatment with 5-FU, potential recall bias, and lack of an objective measure of treatment burden. Still, most stated that they would still continue to seek alternative treatment for AKs in the future and would still be open to other topical treatments, especially if associated with a better safety and tolerability profile than 5-FU. Nonadherence to treatment is a major cause of treatment failure. Particularly, up to 50% of dermatology patients may be nonadherent to treatment regimens [16]. Ineffective communication about treatment-related AEs may predispose patients to poor adherence [16,17]. Prescription of a topical steroid as needed may also help decrease the burden of intolerable skin irritation secondary to 5-FU [18]. Shared decision-making with patients after discussing the benefits and risks of medicines, in addition to therapeutic options, and appropriate counseling may increase adherence and improve patient outcomes [19,20].

Conclusions
Most participants believed that AK is important to treat and had low concern regarding 5-FU at baseline. During treatment, participants experienced both physical and psychosocial burden secondary to topical 5-FU treatment. Although our study was limited by input from participants who refused future treatment with 5-FU, many did not believe that treatment helped their AKs, and inability to assess effectiveness due to premature discontinuation secondary to AE was a common theme. Most stated that they would continue to seek alternative treatment for AKs in the future. Nonadherence is a major cause of treatment-resistant disease. Shared patient-physician decision-making focusing on the benefits and risks of treatment, realistic expectations, therapeutic alternatives, and counseling may increase adherence and improve outcomes.