Field Therapy for Actinic Keratosis: A Structured Review of the Literature on Efficacy, Cost, and Adherence.

BACKGROUND: Although there are evidence-based guidelines for actinic keratosis management, selecting a cost-effective field therapy is challenging because of limited studies comparing cost, efficacy, and adherence among treatments. OBJECTIVE: To review the literature on field-directed therapies for actinic keratosis, comparing efficacy, cost, and adherence data for topical and in-office treatments. MATERIALS AND METHODS: PubMed, Embase, Web of Science, and Google Scholar databases were searched from October 2020 to March 2021 for articles on field therapy for actinic keratosis. Total cost per regimen was estimated using wholesale acquisition cost package prices and Medicare coverage rates for May 2021. Effective cost was approximated by dividing total cost by complete response rate. RESULTS: Efficacy data for various field therapies range widely, and long-term follow-up is limited. Cross-study comparisons are challenging because of heterogeneity of studies. Field-directed therapy with topical 5-fluorouracil and photodynamic therapy have similar effective cost. Adherence may significantly affect real-world efficacy and long-term clearance; this would favor shorter duration topical regimens or in-office procedures. CONCLUSION: Standardization of future studies examining efficacy of field treatments for actinic keratosis will allow comparison across treatments. In-office treatments such as photodynamic therapy represent a cost-effective alternative to topical therapies with comparable efficacy.

Assessment of reflectance confocal microscopy for monitoring treatment of actinic keratosis and field cancerization with daylight photodynamic therapy.

Actinic keratosis (AK) is the most common pre-malignant cutaneous lesion of the skin, often associated with field cancerization. Daylight photodynamic therapy (DL-PDT) is used as treatment, showing good histological results. Reflectance confocal microscopy (RCM) may be useful as a non-invasive, real-time approach to monitor treatment, however, there is a lack of data on the correlation between RCM and histopathological findings in AK patients treated with DL-PDT. To correlate histological and RCM findings and evaluate the efficacy of DL-PDT in patients with AK and field cancerization treated with DL-PDT. Patients with field cancerization and a minimum of six AK lesions on the face were included in the study. A single session combining methyl aminolevulinate followed by two-hour daylight exposure of the face was performed. RCM and biopsy were performed before and after three months of the intervention to compare efficacy between patients using the Wilcoxon test, and concordance of the findings based on the different methods was analysed using the Kappa test. Twenty-four patients completed the study. An improvement in photodamage and a decrease in the number of AK lesions (45.3% reduction) was observed. Regression in atypia and dysplasia was observed via histopathology and RCM, however, there was poor agreement between the methods. No changes were observed after treatment for inflammation, fibroplasia and acantholysis. Concordance between histological and RCM findings was poor, suggesting that RCM cannot replace the histopathological examination, however, it may be used as an adjuvant test for follow-up of patients. Despite this, DL-PDT proved to be an effective method for treating AK.

Patient assessment of 5-fluorouracil and imiquimod for the treatment of actinic keratoses: a retrospective study of real-world effectiveness.

BACKGROUND: Despite the superior efficacy of topical therapies for the treatment of actinic keratoses in clinical trials, cryosurgery remains a frequent treatment modality in clinical practice. Little is known about patients' experience of real-world use of topical therapy. OBJECTIVE: To determine the real-world effectiveness and tolerability of 5-fluorouracil and imiquimod in the treatment of actinic keratoses. METHODS: A phone survey and chart review was conducted among 51 patients prescribed 5-fluorouracil (N = 27) or imiquimod (N = 24) for actinic keratoses. RESULTS: Six patients (22%) in the 5-fluorouracil group and five patients (21%) in the imiquimod group reported severe local skin reactions, and three patients in both groups (11% and 13%, respectively) were unwilling to use the respective topical therapies again. Patients in the 5-fluorouracil group had, on average, 3.3 fewer cryosurgery spot treatments following topical treatment. Patients in the imiquimod group averaged 2.0 fewer spot treatments. LIMITATIONS: While this study provides information on real-world experiences, patients' responses were limited by the ability to recall treatment and potential adverse effects. CONCLUSION: High rates of skin reactions, prolonged discomfort, and the continued need for procedural treatments may make patients less willing to use topical 5-fluorouracil or imiquimod for actinic keratoses.

Efficacy Assessment of the High-Frequency High-Intensity Focused Ultrasound as a New Treatment for Actinic Keratosis.

BACKGROUND: Actinic keratosis (AK) is the most common precancerous cutaneous lesion, with risk of progression to cutaneous squamous cell carcinoma. In the current study, we evaluated the efficacy of 20-MHz high-intensity focused ultrasound (HIFU), as a new treatment modality for AK. MATERIALS AND METHODS: Patients with AK lesions (grades I-III) treated with HIFU were included in the study. The clinical assessment was performed 3 months after therapy. RESULTS: Twenty-one patients (14 men, 7 women) with 108 AK lesions (grades I-III) were included in the current study. Ages ranged from 62 to 85 years (mean 72.6 years). Clinically complete resolution of the actinic damage in the treated area was detected in 72.2% of lesions. Furthermore, 28 lesions (26%) showed a reduction of the AK grade, or partial response, after the therapy. Most of the patients experienced annoying but short pain during the procedure. However, late adverse effects of the therapy, such as hypopigmentation, hyperpigmentation and erythema were reported only in a small portion of the lesions. CONCLUSIONS: 20-MHz HIFU could be an effective and safe alternative treatment for AK.

Utilization of an Online Cash-Pay Pharmacy for Topical 5-Fluorouracil Prescriptions in Older Patients.

BACKGROUND: High cost of prescription medications presents a challenging issue for older patients with multimorbidities. Topical 5-fluorouracil (5-FU) is an effective treatment for actinic keratoses (AK), a highly prevalent condition among elderly populations, but it is often associated with unpredictable retail prices and high out-of-pocket costs. One online pharmacy offers branded prescription medications at fixed, low prices, but it may be less accessible to older patients for numerous reasons. OBJECTIVE: To determine if the number of patients receiving topical 5-FU from an online pharmacy is proportionate to the national data on expected payment types for patients prescribed topical 5-FU for AK. METHODS: We conducted a cross-sectional study using weighted pooled data from the National Ambulatory Medical Care Survey (NAMCS) on topical 5-FU prescriptions for AK from 2007-2016. Data regarding online pharmacy use were provided by Dermatology.com for the year 2019. RESULTS: Among patients with AK prescribed topical 5-FU, the most prevalent payment source was Medicare (54%) followed by private insurance (40%). On the online pharmacy, the majority of patients had commercial insurance (71%) followed by Medicaid (12%). LIMITATIONS: Data from Dermatology.com are limited. CONCLUSIONS: Lower-cost medications from the online pharmacy site may improve adherence and outcomes in older adults and decrease total cost associated with AK treatment. However, the online pharmacy is underutilized by this population. J Drugs Dermatol. 2020;19(4): doi:10.36849/JDD.2020.4690.

Assessment of 5-Aminolaevulinic Acid Photodynamic Therapy (ALA-PDT) in Chinese patients with actinic keratosis: Correlation of dermoscopic features with histopathology.

OBJECTIVES: The study examines the changes in dermoscopic features of actinic keratosis (AK) after photodynamic therapy, and delineates the association between AK dermoscopic and histopathological findings. METHODS: A total of 21 patients (23 lesions) with pathologically confirmed actinic keratosis who received 5-aminolaevulinic acid (ALA) photodynamic therapy (ALA-PDT) were enrolled. The numbers of PDT treatments were: 1, n = 1; 2, n = 2; 3, n = 10; 4, n = 6; 5, n = 2; 6, n = 2). The dermoscopic features before and after the PDT were compared. RESULTS: There were statistically significant decreases in the positive rates of dermoscopic features including scales (P < 0.001), follicular plugs with whitish halo (P = 0.013), and red pseudonetwork (P = 0.022) among patients treated with ALA-PDT. Dermoscopic feature was significantly associated with pathological grade (P < 0.001). Histopathological hyperkeratosis was significantly associated with dermoscopic red pseudonetwork (P = 0.034) and wavy vessel (P = 0.005). Parakeratosis was associated with wavy vessels (P = 0.001). For vascular hyperplasia in dermal papillae, the significant correlates included scales (P = 0.011), follicular plugs with whitish halo (P = 0.011), red pseudonetwork (P < 0.001); coiled vessels (P = 0.003) and rosette sign (P = 0.004). Wavy vessels was the only feature correlating keratosis pilaris (P = 0.003). CONCLUSIONS: The findings of the present study support dermoscopy as having potential to be useful for diagnosing and monitoring of actinic keratosis.

A trial-based cost-effectiveness analysis of topical 5-fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the head and neck area performed in the Netherlands.

BACKGROUND: Actinic keratosis (AK) is a common premalignant skin condition that might have the ability to progress into squamous cell carcinoma. Due to the high incidence of AK, treatment of this disease significantly impacts healthcare spending. OBJECTIVES: To determine which commonly prescribed field-directed treatment is the most cost-effective, when comparing 5-fluorouracil (5-FU) 5%, imiquimod (IMQ) 5%, ingenol mebutate (IM) 0·015% and methyl aminolaevulinate photodynamic therapy (MAL-PDT) for AK in the head and neck region. METHODS: We performed an economic evaluation from a healthcare perspective. Data were collected alongside a single-blinded, prospective, multicentre randomized controlled trial with 624 participants in the Netherlands. The outcome measure was expressed as the incremental cost-effectiveness ratio, which is the incremental costs per additional patient with ≥ 75% lesion reduction compared with baseline. This trial was registered at ClinicalTrials.gov, number NCT02281682. RESULTS: The trial showed that 5-FU was the most effective field treatment for AK in the head and neck region. Twelve months post-treatment, the total mean costs for 5-FU were significantly lower (€433) than the €728, €775 and €1621 for IMQ, IM and MAL-PDT, respectively. The results showed that 5-FU was a dominant cost-effective treatment (more effective and less expensive) compared with the other treatments, 12 months post-treatment. CONCLUSIONS: Based on these results, we consider 5-FU 5% cream as the first-choice treatment option for multiple AKs in the head and neck area. What's already known about this topic? Due to the increasing incidence of actinic keratosis (AK), the recommended treatment results in a considerable socioeconomic burden for (dermatological) healthcare. Although cost-effectiveness modelling studies have been performed in which different treatments for AK were compared, a prospective clinical trial comparing four frequently prescribed treatments on effectiveness and resource consumption within a time horizon of 12 months has never been conducted. What does this study add? This is the first study examining the cost-effectiveness of 5-fluorouracil 5% cream, imiquimod 5% cream, ingenol mebutate 0·015% gel and methyl aminolaevulinate photodynamic therapy, with data collected in a randomized controlled trial over a time horizon of 12 months. We found that 5-fluorouracil was a dominant cost-effective treatment (more effective and less costly), based on data from the Netherlands. Linked Comment: Steeb et al. Br J Dermatol 2020; 183:612.

Comparison of efficacy, adverse effects and costs between 20 % ALA-PDT and 10 % ALA-PDT for the treatment of actinic keratosis in Chinese patients.

BACKGROUND: 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) is a reliable treatment for actinic keratosis (AK), though the concentration of 20 % is applied in most ALA-PDT for the treatment of AK, it was found that 10 % ALA could achieve similar outcome during clinical practice. However, there are limited number of reports comparing the efficacy and the safety of ALA-PDT with different ALA doses when treating AK. OBJECTIVES: This study was designed to compare the efficacy, the adverse effects and the costs of 10 % and 20 % ALA-PDT for AK treatment. METHODS: We reviewed the records of patients who had received ALA-PDT in our department between January 1, 2012, and April 30, 2017, the efficacy, the adverse effects were recorded, and the costs were analyzed. Follow-up data were collected until April 30, 2018. RESULTS: A total of 59 AK patients' records were analyzed for the efficacy, the adverse events, the recurrence and the costs. All the AK lesions were tapped with plum-blossom needle as a pre-treatment before receiving ALA-PDT. There was no statistical difference between 10 % ALA-PDT and 20 % ALA-PDT in terms of efficacy and adverse events. In the 10 % ALA group, there was one recurrence out of 34 patients and in the 20 % group there were none. The average treatment cost of each lesion was significantly lower in 10 % ALA group than in 20 % ALA group. CONCLUSIONS: 10 % ALA-PDT has similar efficacy and adverse effects as 20 % ALA-PDT with lower costs. Taken together, this supports the use of 10 % ALA-PDT in clinical practice.

Modeling PpIX effective light fluence at depths into the skin for PDT dose comparison.

BACKGROUND: Daylight-activated PDT has seen increased support in recent years as a treatment method for actinic keratosis and other non-melanoma skin cancers. The inherent variability observed in broad-spectrum light used in this methodology makes it difficult to plan and monitor light dose, or compare to lamp light doses. METHODS: The present study expands on the commonly used PpIX-weighted effective surface irradiance metric by introducing a Monte Carlo method for estimating effective fluence rates into depths of the skin. The fluence rates are compared between multiple broadband and narrowband sources that have been reported in previous studies, and an effective total fluence for various treatment times is reported. A dynamic estimate of PpIX concentration produced during pro-drug incubation and treatment is used with the fluence estimates to calculate a photodynamic dose. RESULTS: Even when there is up to a 5x reduction between the effective surface irradiance of the broadband light sources, the effective fluence below 250 µm depth is predicted to be relatively equivalent. An effective threshold fluence value (0. 70Jeff/cm2) is introduced based on a meta-analysis of previously published ALA-PpIX induced cell death. This was combined with a threshold PpIX concentration (50 nM) to define a threshold photodynamic dose of 0.035 u M Jeff/cm2. CONCLUSIONS: The threshold was used to generate lookup tables to prescribe minimal treatment times to achieve depth-dependent cytotoxic effect based on incubation times and irradiance values for each light source.

5-aminolaevulinic acid nanoemulsion is more effective than methyl-5-aminolaevulinate in daylight photodynamic therapy for actinic keratosis: a nonsponsored randomized double-blind multicentre trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) with methyl-5-aminolaevulinate (MAL) is an effective treatment for mild and moderate actinic keratosis (AK). OBJECTIVES: To assess the clinical efficacy, tolerability and cost-effectiveness of 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) compared with MAL in DL-PDT for grade I-II AKs. METHODS: This nonsponsored, prospective randomized double-blind multicentre trial included 69 patients with 767 grade I-II AKs located symmetrically on the face or scalp. A single DL-PDT was given in a randomized split-face design. The primary outcome was clearance of the AKs at 12 months as assessed by a blinded observer. The secondary outcomes were pain, treatment reactions, cosmetic outcome and the cost-effectiveness of the therapy. RESULTS: In the per-patient (half-face) analysis, clearance was better for the BF-200 ALA sides than for those treated with MAL (P = 0·008). In total, BF-200 ALA cleared 299/375 AKs (79·7%) and MAL 288/392 (73·5%) (P = 0·041). The treatment was practically painless with both photosensitizers, the mean pain visual analogue scale being 1·51 for BF-200 ALA and 1·35 for MAL (P = 0·061). Twenty-six patients had a stronger skin reaction on the BF-200 ALA side, seven on the MAL side and 23 displayed no difference (P = 0·001). The cosmetic outcome was excellent or good in > 90% of cases with both photosensitizers (P = 1·000). The cost-effectiveness plane showed that the costs of DL-PDT were similar for both photosensitizers, but the effectiveness was slightly higher for BF-200 ALA. CONCLUSIONS: Our results indicate that BF-200 ALA is more effective than MAL in DL-PDT for grade I-II AKs. BF-200 ALA provides slightly better value for money than MAL.

Evaluation of the treatment costs and duration of topical treatments for multiple actinic keratosis based on the area of the cancerization field and not on the number of lesions.

BACKGROUND: The cost of topical treatments for actinic keratosis (AK) has historically been evaluated in relation to the number of lesions requiring treatment or simply by the price of a single tube/sachet of the drug used. OBJECTIVE: To demonstrate a new method of costing topical treatments in AK, which takes into account the actual cancerization area treated. METHODS: In order to evaluate the actual cost of each treatment, the official approval status of the drug was used to estimate the amount of cream needed per one cm2 . This value was then applied to the hypothetical cancerization area sizes to demonstrate the impact of the size treated on the actual cost of treatment. The price considered was the ex-factory price in Italy. RESULTS: Areas which could be treated with a single tube/sachet of Metvix® , Picato® , Aldara® , Solaraze® and Zyclara® were 200, 25, 25, 33.3 and 200 cm2 , respectively. For the treatment of smaller areas (<100 cm2 ), treatment with Metvix® was the most costly topical option in Italy. However, for the treatment of cancerization areas larger than 100 cm2 , Metvix® was the least expensive treatment option. Treatment with Metvix® was least long, requiring a single day of treatment for an area of up to 200 cm2 , compared with up to 224 days of treatment with Aldara® for the treatment of a similar size. CONCLUSION: Changing treatment costing strategy in the management of multiple AKs towards costing per cancerization area instead of costing per lesion is a much more accurate representation of the 'real world cost' for AK.

Evaluation of the costs of topical treatments for actinic keratosis based on lesion response and the affected area.

BACKGROUND: The cost of topical treatments for actinic keratosis (AK) has never been evaluated with respect to the actual cancerization field treated and the corresponding lesion response rate. Traditionally, evaluation in AK has been done in the context of patient response rate alone. The current study aimed to develop an economic model assessing the cost of topical treatments for the management of AK in Italy. METHODS: Data from Italian patients (N.=100) with five or more mild/moderate lesions on the face and/or scalp was used. The efficacy of the topical treatments which are available for the treatment of AK in Italy was considered. The outcome of interest was lesion response rates at three months and was based on published literature. The cost of each treatment was estimated according to the approval status of the drug and the cancerization area that required treatment. The analysis was replicated for four other European countries. RESULTS: The average costs of treatment with c-PDT, DL PDT, DHA, InMeb and IMQ were € 364.2, € 255.5, € 848.7, € 1039.1, and € 628.3, respectively. Taking into account the number of lesions cleared per patient, the cancerization area treated, and the number of visits required with each treatment, the total costs per lesion treated per patient were estimated at € 37.9, € 29, € 264.7, € 103.5, and € 115.4, respectively. The analysis produced consistent results when it was replicated for other countries. CONCLUSIONS: Daylight therapy with methyl aminolevulinate (DL PDT) is an effective treatment option for AK management with a favourable value for money profile.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

In vivo Confocal Laser Microscopy for monitoring of actinic keratosis treatment: a comparison with histopathologic assessment after treatment with topical 5% 5-fluorouracil.

BACKGROUND: Histological examination is the gold standard for actinic keratosis diagnosis; however, it is not always a feasible approach. Reflectance confocal microscopy (RCM) is a non-invasive technique that may be an alternative for monitoring actinic keratoses treatment response. Topical 5-fluorouracil is indicated for actinic keratosis multiple lesions and for field cancerization treatment. OBJECTIVES: To assess the RCM accuracy, sensibility and specificity for actinic keratosis, considering as a gold standard the histopathological examination; as well as to evaluate the efficacy of 5% 5-fluorouracil treatment. METHODS: This is a prospective study in actinic keratosis patients between August 2014 and November 2015. RCM analyses were performed in one randomly selected actinic keratosis lesion of the upper limbs by two independent observers before and after 5% 5-fluorouracil treatment. At the end of treatment and with clinical bleaching of treated lesions, histological examination was performed by two pathologists. RESULTS: A total of 50 lesions were enroled, and 40 lesions presented complete clinical bleaching after treatment and were included in the final analysis. Accuracy, sensibility and specificity means among observers were 83.8%, 84.6% and 83.3%, respectively. After 5-fluorouracil treatment, actinic keratosis was diagnosed in 45.0% (observer 1) and 32.5% (observer 2) of subjects according to RCM and in 32.5% of subjects according to histological examination. Considering RCM observers diagnosis, the concordance was substantial (k 0.637, P < 0.001). 5-fluorouracil led to a reduction in 55.0%-67.5% of actinic keratoses according to RCM analysis. CONCLUSION: This study allows to validate RCM as a non-invasive method capable of monitoring actinic keratosis therapeutic response to 5-fluorouracil, presenting efficacy comparable to histological examination. Additionally, the results suggest that 5-fluorouracil may be a satisfactory option for therapeutic control of this condition.

Assessment of Efficacy and Irritation of Ingenol Mebutate Gel 0.015% Used With or Without Dimethicone Lotion for Treatment of Actinic Keratosis on the Face.

Background: Ingenol mebutate gel 0.015% provides high clearance rates for actinic keratosis (AK) on the face and scalp but causes transient local skin responses (LSRs).

Objective: This study sought to determine whether the application of 1% dimethicone would decrease ingenol mebutate-associated LSRs and/or affect efficacy during the treatment of multiple AKs on the face.

Methods: Ingenol mebutate gel 0.015% was applied for 3 days to two 25 cm2 areas, each containing 3 to 8 AKs on the face of each subject, followed by application of 1% dimethicone lotion in an investigator-blinded manner to one randomly selected AK-containing area until LSRs were no longer present.

Results: In total, 20 subjects were enrolled and completed the study. Topical 1% dimethicone lotion applied during and after treatment of facial AK with ingenol mebutate gel 0.015% reduced mean total LSR scores at days 8 and 15 compared with ingenol mebutate gel only, although the difference was not statistically significant. Efficacy was equivalent between the two treatment arms.

Limitations: The study evaluated a relatively small number of subjects, all of whom were white.

Conclusions: The application of 1% dimethicone following ingenol mebutate gel 0.015% produced a trend toward lower severity of some LSRs, with no difference in efficacy.

J Drugs Dermatol. 2017;16(5):432-436.