Skin Cancers in Medicare Beneficiaries With Actinic Keratoses.

Importance: Actinic keratoses (AK) are common premalignant skin lesions with a small risk of progressing to cutaneous squamous cell carcinoma (SCC). There is some evidence that patients with AKs also have increased risks of other skin cancers beyond SCC. However, the absolute risks of skin cancer in patients with AKs are unknown. Objective: To calculate the absolute and relative risks of future skin cancer in Medicare beneficiaries with AKs. Design, Setting, and Participants: This retrospective cohort study was performed using a deidentified, random sample of 4 999 999 fee-for-service Medicare beneficiaries from 2009 through 2018. Patients with treated AKs were included, and patients with seborrheic keratoses (SKs) were included as a comparator group. All patients were required to have at least 1 year between data set entry and first AK or SK. Patients with a history of skin cancer were excluded. Data were analyzed from September 2022 to March 2023. Main Outcomes and Measures: Outcomes were first surgically treated skin cancer, including keratinocyte carcinoma (including SCC and basal cell carcinoma [BCC]) and melanoma. The absolute risks of skin cancer in patients with AKs were evaluated. Skin cancer risks in patients with AKs were compared with patients with SKs using adjusted competing risks regression. Results: A total of 555 945 patients with AKs (mean [SD] age, 74.0 [7.4] years; 55.4% female) and 481 024 patients with SKs (mean [SD] age, 73.3 [7.3] years; 72.4% female) were included. The absolute risk of skin cancer after a first AK was 6.3% (95% CI, 6.3%-6.4%) at 1 year, 18.4% (95% CI, 18.3%-18.5%) at 3 years, and 28.5% (95% CI, 28.4%-28.7%) at 5 years. Patients with AKs had increased risk of skin cancer compared with patients with SKs (any skin cancer: adjusted hazard ratio [aHR], 2.17; 95% CI, 2.15-2.19; keratinocyte carcinoma: aHR, 2.20; 95% CI, 2.18-2.22; SCC: aHR, 2.63; 95% CI, 2.59-2.66; BCC: aHR, 1.85; 95% CI, 1.82-1.87; and melanoma: aHR, 1.67; 95% CI, 1.60-1.73). Conclusions and Relevance: In this cohort study, older patients with AKs had substantial absolute risks, as well as elevated relative risks, of skin cancer. AKs may be clinical markers of UV exposure and increased skin cancer risk, including SCC, BCC, and melanoma. However, guidelines are lacking for follow-up skin cancer surveillance in patients with AKs. Efforts to develop evidence-based recommendations for skin cancer surveillance in patients with AKs are paramount.

Artificial intelligence-based PRO score assessment in actinic keratoses from LC-OCT imaging using Convolutional Neural Networks.

BACKGROUND AND OBJECTIVES: The histological PRO score (I-III) helps to assess the malignant potential of actinic keratoses (AK) by grading the dermal-epidermal junction (DEJ) undulation. Line-field confocal optical coherence tomography (LC-OCT) provides non-invasive real-time PRO score quantification. From LC-OCT imaging data, training of an artificial intelligence (AI), using Convolutional Neural Networks (CNNs) for automated PRO score quantification of AK in vivo may be achieved. PATIENTS AND METHODS: CNNs were trained to segment LC-OCT images of healthy skin and AK. PRO score models were developed in accordance with the histopathological gold standard and trained on a subset of 237 LC-OCT AK images and tested on 76 images, comparing AI-computed PRO score to the imaging experts' visual consensus. RESULTS: Significant agreement was found in 57/76 (75%) cases. AI-automated grading correlated best with the visual score for PRO II (84.8%) vs. PRO III (69.2%) vs. PRO I (66.6%). Misinterpretation occurred in 25% of the cases mostly due to shadowing of the DEJ and disruptive features such as hair follicles. CONCLUSIONS: The findings suggest that CNNs are helpful for automated PRO score quantification in LC-OCT images. This may provide the clinician with a feasible tool for PRO score assessment in the follow-up of AK.

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.

Method of Assessing Skin Cancerization and KeratosesTM (MASCK™): development and photographic validation in multiple anatomical sites of a novel assessment tool intended for clinical evaluation of patients with extensive skin field cancerization.

BACKGROUND: A range of 'field-directed' treatments is available for the management of extensive skin field cancerization (ESFC), but to date, the only validated objective quantitative tools are limited to assessment of actinic keratoses (AKs) affecting the head. AIMS: To develop a versatile quantitative instrument for objective clinical assessment of ESFC and perform initial internal validation across multiple anatomical zones. METHODS: The study comprised instrument development, pilot testing and instrument refinement and two rounds of reliability and inter-rater validation testing. The study was noninterventional and used a convenience sample of de-identified patient photographs selected based on preset criteria. An expert panel developed the instrument and scoring system via a modified Delphi voting process. A sample of 16 healthcare professionals from multiple specialties undertook the pilot testing, and a panel of seven dermatologists were involved in validation testing. Validation was determined by assessment of overall inter-rater agreement using Gwet chance-corrected agreement coefficients (ACs). RESULTS: The instrument produced, called the Method for Assessing Skin Cancer and Keratoses™ (MASCK™), comprises the Skin Field Cancerization Index (SFCIndex), derived from area of skin involvement and AKs (number and thickness), a global assessment score and a cancer-in-zone score, and uses Likert scales for quantitative scoring. The SFCIndex is a composite score comprising the number and thickness of AKs multiplied by area of skin involvement. ACs for the SFCIndex components, the overall SFCIndex score and the global assessment score were > 0.80 (rated 'almost perfect') while the AC for the cancer-in-zone metric was lower (0.33, rated 'fair'). Internal consistency was demonstrated via positive correlation between the overall SFCIndex score and the global assessment score. CONCLUSIONS: Our study found near-perfect agreement in inter-rater reliability when using MASCK to assess the severity of ESFC in multiple anatomical sites. Further validation of this novel instrument is planned to specifically assess its reliability, utility and feasibility in clinical practice.

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.

Treating Field Cancerization by Ablative Fractional Laser and Indoor Daylight: Assessment of Efficacy and Tolerability.

Objective: To assess if ablative fractional laser combined with indoor daylight photodynamic therapy are effective and safe for the treatment of skin field cancerization associated with actinic keratosis (AK). Methods: A total of 46 patients with field cancerized skin and AK were treated by a single session of laser assisted drug delivery (LAAD) and indoor daylight photodynamic therapy (IDL-PDT). LAAD was applied using a CO2 ablative fractional laser (AFXL) and aminolevulonic acid. Thereafter, IDL-PDT was administered using a novel device that mimics the sun radiation with a total dose of 48 J/cm². Results: All patients showed remission following subsequent to the study protocol (complete: 71.7%, partial: 28.3%). Pain scores using a visual analog scare immediately following treatments were 9.0 ± 2.0. Conclusions: AFXL-LAAD combined with IDL-PDT is extremely effective for the treatment of skin field cancerization associated with AK. Nevertheless, the high pain scores associated with this combined approach may prove to be a limiting factor. Thus, further protocol modifications in larger scale studies are still warranted. J Drugs Dermatol. 2020;19(3):425-427. doi:10.36849/JDD.2020.4589.

Quality assessment of a large primary GP skin cancer service in Auckland, New Zealand.

AIM: Waitemata District Health Board has implemented a new approach to the management of skin cancers by triaging lesions to specialist-trained general practitioners (GPSI) with the aim of reducing patient wait times and treatment costs. The primary outcome was to determine positive margin rates for the GP surgeons, with secondary outcome being infection rates. METHOD: A retrospective audit was conducted on all excisions (n=2,705) performed between 1 January 2016 and 31 December 2016 by the 13 WDHB GPSIs. Electronic patient records were accessed to review data. Each lesion was classified into benign, in-situ (pre-malignant) and malignant categories. Surgical margins were analysed for non-melanotic skin cancers (NMSC) and determined as positive, close or negative. Infection rates determined by microbiology results and prescribing information and time to treat analyses were conducted. RESULTS: WDHB GPSIs performed 2,705 excisions, 1,887 (69.8%) of which were malignant lesions. Among the 1,486 NMSC excised, a positive surgical margin was observed in 51 (3.4%). There were 294 (10.9%) cases of infection in 2,705 excisions. Median time to treat was 31 days across all lesions. New Zealand papers from the last two decades estimate the NMSC positive margin rate among primary care physicians varies between 16-31%; most recent papers have published rates 6.8-9.5%.European publications describe positive margin rates ranging between 13.9-33.5%. CONCLUSION: This study validates the use of surgically trained GP surgeons and shows their integral role in managing the high volume of skin cancer in New Zealand.

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.