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Actinic keratosis. Distribution of maximum composite LSR scores in phase III studies (safety population). LSR Local skin response
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Introduction:
Local skin responses (LSRs) are the most common adverse effects of topical actinic keratosis (AK) therapy. There is currently no method available that allows objective characterization of LSRs. Here, the authors describe a new scale developed to quantitatively and objectively assess the six most common LSRs resulting from topical AK...
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Background:
Actinic keratoses (AK) are common skin lesions that can progress to invasive squamous cell carcinoma of the skin. A variety of lesion- or field-targeted treatment options exist and their efficacy has been demonstrated in numerous randomised controlled trials (RCTs). However, the reported endpoints are highly heterogeneous, making it di...
Background: Actinic keratosis (AK) is characterized by the occurrence of thick and scaly skin areas caused by damage from ultraviolet radiation. The management of AK aims to reduce lesions and prevent their recurrence by regular monitoring. French guidelines, last updated in 2009, reflect European guidelines for the management of face and scalp AK....
Background:
Clinical diagnosis of actinic keratosis is known to have intra- and inter-observer variability, and there is currently no non-invasive and objective measure to diagnose these lesions.
Objective:
The aim of this pilot study was to determine if automatically detecting and circumscribing actinic keratoses in clinical photographs is feas...
Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide, and exposure to ultraviolet (UV) light is a major cause of SCC. UV nail lamps can be used for drying and hardening acrylic or gel nail polish. We report a case of a 52-year-old Caucasian woman with an 18-year history of UV nail lamp use every 3 weeks and an 18-year histo...
Actinic keratosis represents the earliest manifestation of non-melanoma skin cancer. Because of their risk of progression to invasive squamous cell carcinoma, an earlier diagnosis and treatment are mandatory. Their diagnosis sometimes could represent a challenge even for expert dermatologists. Dermoscopy, confocal laser microscopy and optical coher...
Citations
... The severity of LSRs was assessed by determining the LSR total score at week 4 (or before, in case of a major local reaction). For the LSR total score, six objective items (erythema, flaking/scaling, crusting, swelling, vesiculation/postulation and erosion/ulceration) were each assessed on a 5-point scale from 0 to 4 (0: none; 1: mild; 2: moderate; 3: moderately severe; and 4: severe), yielding a composite score ranging from 0 (best outcome possible) to 24 (worst outcome possible) [24]. The LSR total score was recorded at each study visit for each patient. ...
Introduction:
Topical 5-fluorouracil (5-FU)-containing treatments are effective for actinic keratosis (AK); however, they frequently lead to transient local skin reactions (LSRs), which often result in treatment non-adherence.
Methods:
The aim of this international, phase IV clinical trial was to investigate whether addition of an emollient to topical 4% 5-FU would reduce the frequency and severity of LSRs over 4 weeks of treatment (intervention group) compared with 4% 5-FU alone (control group) in patients with AK. The primary objective was to assess the severity of LSRs (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) at week 4 of treatment (or before, in case of a major local reaction). Key secondary objectives were LSR total scores at weeks 2 and 8, the scores of individual LSR items at each visit, and the proportions of patients with 100% and ≥ 75% AK lesion clearance at week 8.
Results:
In total, 141 patients were included in the efficacy analysis (71 in the intervention group and 70 in the control group). There were no statistically or clinically significant differences between the treatment groups in terms of LSR total score at week 4 (overall and by subgroups defined by the number of lesions and patient age at baseline), scores of individual LSR items at any time point, and AK lesion clearance rates at week 8. LSR scores with topical 4% 5-FU alone were lower than expected. Skin reactions were the most common treatment-emergent adverse events in both groups, leading to treatment discontinuation in nine patients (12.3%) in the intervention group and seven (9.9%) in the control group. No new safety signals were observed with the addition of an emollient to 4% 5-FU.
Conclusions:
Daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 4% 5-FU.
... Skin reactions in the target area will be scored using the LSR scale developed for AK. 19 The scale is used to measure multiple components of possible skin responses to the trial product. It measures presence and severity (0-4) of six clinical characteristics that are commonly observed LSRs in relation to topical therapies (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration). ...
Introduction
Actinic keratosis (AK) is the most common precancerous skin condition caused by long-term UV exposure. Given the high recurrence rate of 15%–53%, identifying safe and effective treatment options is warranted. AVX001, a cytosolic phospholipase A 2 α (cPLA 2 α) enzyme inhibitor, is a novel anti-inflammatory drug for field-directed, self-administered, topical therapy of AK.
Methods and analysis
This study is a single-centre, randomised, vehicle-controlled, double-blind, parallel-group hybrid clinical trial in adults with multiple AK lesions Olsen grade 1 or 2. The hybrid design combines decentralised participant tasks and assessments with conventional in-clinic visits. Recruitment using targeted advertising on social media and eligibility prescreening are conducted via the Studies&Me online recruitment platform. Participants (n=60) are randomly assigned to 1 of 3 treatment arms: AVX001 gel 1%, AVX001 gel 3% or vehicle gel. The trial consists of a 4-week treatment period with daily field-directed topical application of the gel and an 8-week follow-up period. Participants attend in-clinic visits at baseline, week 4 and week 12. The remote participant trial tasks include questionnaires and upload of smartphone-obtained photos of the treated skin area using a study-specific web-based app. Both remote and in-clinic assessments of safety and efficacy will be performed. The primary objective is to evaluate the local tolerability of daily application of AVX001 gel (1% or 3%) compared with vehicle gel. Secondary objectives include safety, efficacy, dose–response efficacy relationship, treatment satisfaction and cosmetic outcome. Exploratory objectives include evaluations of tolerability and efficacy assessed by dermatologists using smartphone photos uploaded by participants, comparisons of in-clinic and remote assessments and assessment of AK-related skin changes by non-invasive optical imaging.
Ethics and dissemination
Approved by the Ethics Committee of the Capital Region of Denmark (H-21018064) and the Danish Medicines Agency (2021032485). Results will be submitted for publication in peer-reviewed scientific journals.
Trial registration numbers
2021-000934-32; NCT05164393 .
... Local reactions, defined as erythema, flaking or scaling, crusting, swelling, vesiculation or pustulation, or erosions or ulceration, 15 16 In addition, a composite score was calculated as the sum of the scores for all six signs (range, 0 to 18, with higher scores indicating more severe reactions) at each visit for each patient. ...
Background
The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma.
Methods
In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm² contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]).
Results
A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved.
Conclusions
In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.)
VISUAL ABSTRACT
Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis
... A fourth grade could be defined as a grade III very advanced and presenting vesiculation/erosion in addition [148]. ...
... This necessity has been showed during daylight PDT treatment which consists in not using a laser with a special wavelength that could be costly or painfull but rather using the sunlight which allows to excitate PpIX continuously [146]. Daylight MAL-PDT (Metvix ® cream) is starting 505 to be used for actinic keratosis and displays good clearance rate after three months, 77 % when sun-exposed 244 min (30 patients) [147] or 77 % when sun-exposed 150 min (120 patients) [148]. ...
Non-melanoma skin cancers are on the rise with 2 to 3 million people diagnosed each year and are sometimes treated by local ablation therapy. To avoid this surgery, photodynamic therapy (PDT) appears as an advantageous treatment. Currently used in clinics, PDT consists of applying a cream containing a photosensitive precursor to the damaged skin, which, then metabolizes and under light excitation inducescell death. However, this technique is not fully effective if the skin lesion extends into the deep skin layers. To improve the therapeutic treatment of this type of skin cancer, a patch with dissolving microneedles (MNs) was develop to reach the deep layers of lesions that are difficult to treat. Hyaluronic acid, known for its biocompatibility, solubility and biodegradability, was chosen as the constituent material, and mixed with the 5-aminolevulinic acid (photosensitive precursor, 5-ALA). To ensure the best penetration without causing pain by touching the nerve endings, an optimal “pencil-tip” design was defined with MNs length going from 400 to 750μm. A simple and robust manufacturing process called solvent casting molding method, has been set up which is an asset for potential industrialization. In absence of realistic skin lesions model,we chose to establish one on rats skin by applying daily UV-B doses. Histology and pharmacokinetic studies validated the presence of precancerous skin lesions and the MN-patch in vivo efficiency was therefore tested. After one hour application on the injured rat skin, the MN-patch dissolved and released the 5-ALA that further metabolized to protoporphyrin IX (PpIX). A significant level of PpIX fluorescence was recorded suggesting that after light excitation, a PDT session could be effective. In parallel, to reduce pain felt during PDT treatment, a light device with suitable optical and thermal properties was conceived and coupled to the MN-patch. The idea would be to start the illumination directly after MN-patch application in order to avoid a painful photochemical reaction. This wearable and easy to use system purpose a all-in-one PDT processing which fulfills the criterion of patient compliance, better efficiency and speed of treatment.
... LSR. LSR evaluation was conducted at baseline and on days 1, 3-5, 14, 30, and month 3, according to six parameters: redness, edema, flaking, crusting, pustules, and erosion. Each parameter was graded on a standardized 5-point severity scale (0-4) representing none, mild, moderate, prominent, and severe [34]. A total composite score reflecting overall LSR severity was then calculated based on the sum of all parameters (max score: 24). ...
Background and Objectives: Rising incidences of basal cell carcinoma (BCC) have increased the need for effective topical therapies. By enhancing cutaneous uptake of the chemotherapeutic agents, cisplatin and 5‐fluorouracil (5‐FU), laser‐assisted delivery may provide a new combi- nation treatment for BCC. Accordingly, this study aimed to evaluate tumor response, safety, and drug bio- distribution in tumors and blood after topical laser‐ assisted 5‐FU + CIS treatment in BCC patients.
Study Design/Materials and Methods: This open‐ label, proof‐of‐concept trial investigated laser‐assisted combination cisplatin + 5‐FU treatment in 20 patients with histologically verified, low‐risk superficial or nodular BCCs on the face (<20mm) or trunk/ extremities (<50 mm). After tumor demarcation guided by optical co- herence tomography (OCT), BCCs were exposed to abla- tive fractional CO2 laser followed by 60 minutes topical cisplatin solution and 7‐day exposure to 5% 5‐FU cream under occlusion. After 30 days, treatment was repeated if any tumor residual was identified. Tumor response at day 30 and month 3 was assessed clinically as well as by OCT, reflectance confocal microscopy, and ultrasound, supple- mented by histological verification at 3 months. Local skin reactions (LSRs) and side effects were evaluated on days 1, 3–5, 14, 30, and month 3. Drug detection in tumors and blood was performed in a subset of patients 1‐ and 24 hours after treatment.
Results: Nineteen patients completed the trial, with 32% (6/19) receiving a single treatment and 68% (13/19) treated twice. At 3 months, clinical clearance was seen in 18/19 patients with a corresponding 94% (17/18) achieving histological clearance. Baseline tumor thickness and subtype did not influence treatment number or clearance rate (P ≥ 0.61). LSRs were well‐tolerated and consisted of erythema, edema, and erosion, followed by crusting by day 14. Erythema declined gradually by month 3, with 94% of patients and 79% of physicians rating cosmesis as
“good” or “excellent.” Scarring or hyperpigmentation was noted in 50% and 56%, respectively, while pain and in- fection were not observed during the follow‐up period. Although chemotherapy uptake was visualized extending to deep skin layers, no systemic exposure to cisplatin or 5‐FU was detected in patient blood.
Conclusion: Laser‐assisted cisplatin+5‐FU shows potential as an effective and tolerable treatment option for low‐risk BCC, particularly in instances where self‐ application is not possible or where in‐office, non‐surgical therapy is preferred.
... The composite LSR score was then calculated (ranging from 0 to 24). 15 ...
Recently 5‐fluorouracil 0.5% / salicylic acid 10% (5‐FU/SA) topical solution has been included in the National Italian portfolio for lesion‐directed treatment of grade I/II actinic keratosis (AKs) located on the face or scalp. To describe the utility of dermoscopy and RCM in treatment response monitoring of a series of AKs treated with 5‐FU/SA as lesion‐directed therapy. Consecutive patients were prospectively treated for a maximum of 12 weeks with 5‐FU/SA for AKs located on the face or scalp. Clinical, dermoscopic and confocal images of one index AK were acquired at each visit and pre‐specified criteria were evaluated. Clinical, dermoscopic and confocal responses were evaluated at last follow up visit. Fourteen patients were enrolled, of which five were treated for 12 weeks, 7 for 8 and 2 for 4 weeks. At a median follow up of 30 weeks, 64.3% (9/14) index AKs achieved complete clinical, 50% (7/14) complete dermoscopic and 42.9% (6/14) complete confocal clearance. Local skin reaction was mild and significantly decreased during therapy administration. Although the small number of cases, our study underlines the utility of both dermoscopy and in‐vivo RCM in 5‐FU/SA treatment response monitoring for AKs located on the face or scalp.
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... The levels and values of the LSR composite scores obtained were not associated to the treatment efficacy. These results are in accordance with previous research [37,38]. ...
Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.
... Secondary outcomes were AK complete response rates (CR), safety, cosmesis, and OCT-evaluated skin roughness and epidermal thickness. Safety was evaluated as local skin reactions (LSR) including erythema, edema, scaling, pustules, crusting, and erosion scored after 5-7 days on a standardized visual and descriptive 5-point categorial scale [31]. A composite LSR score was calculated as the sum of all parameters (maximum 30 points) [32]. ...
Background and objectives:
Décolleté photodamage is a common condition typically treated with light and energy-based devices. This study investigated the efficacy and safety of a fractional 1,927 nm thulium laser (TL) alone and combined with photodynamic therapy (PDT).
Study design/materials and methods:
In a 12-week follow-up study, participant décolletés were divided into four treatment areas and randomized to receive a single treatment with field-directed TL, PDT, combination TL-PDT, or lesion-directed curettage control. All actinic keratoses (AKs) underwent lesion-directed curettage before randomization. TL was delivered at 20 mJ/mb, 500 mJ/cm2 fluence, 5 W, and 8 (n = 6 pts.) or 16 (n = 6 pts.) passes. PDT was performed with 16% methyl aminolevulinate (MAL) creme incubated for 3 h, followed by red light-emitting diode light at 37 J/cm2 . Outcome measures included clinical assessment of overall photodamage and specific subcomponents, assisted by optical coherence tomography (OCT) imaging.
Results:
Twelve women with moderate to severe photodamage on the décolleté and a cumulative total of 184 thin grade I AKs were included. Field-directed treatments TL and combination TL-PDT equally improved the overall photodamage, mottled pigmentation, and rhytides compared with lesion-directed control (P < 0.05). The skin texture improved by TL alone and was further improved by combining TL and PDT (P < 0.05). Median AK complete responses were similar for field-directed interventions TL-PDT (100%), TL (90%), PDT (82%), and lesion-directed curettage control (52%) (P = 0.464). Patients presented with mild local skin responses, slightly more pronounced when combining TL with PDT versus individual treatments (P < 0.05). No scarring or adverse events were observed.
Conclusions:
The 1,927 nm fractional thulium laser is an effective, tolerable, and safe field-directed treatment for décolleté photodamage. Provided alone, TL proved to be as effective as combined TL-PDT for overall photodamage, while a greater improvement in skin texture was achieved using TL and PDT in combination. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
... Studies with ingenol mebutate gel 0.015% (IngMeb) mostly use composite scores to assess severity of LSRs. Each of six LSR parameters-erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration is graded from 0 to 4, giving a maximum composite score of 24 [15,29]. Jim On et al. [16] reported data of two multicenter, randomized, parallel-group, double-blind, vehicle-controlled studies, involving face and scalp and classified patients with a composite score of 12 or higher as having a severe LSR. ...
Actinic keratoses (AKs) are common lesions on chronically sun damaged skin, which are morphologically characterized by lower third to full thickness atypia of epidermal keratinocytes. These lesions carry a risk of progression towards invasive squamous cell carcinoma (SCC); therefore, treatment of visible lesions and the field in case of field cancerization is recommended. Treatment of AK includes the destruction of atypical keratinocytes that clinically presents with various degrees of erythema, scaling, crusting, erosion, and other visible and subjective symptoms. Such inflammatory reactions may have an impact on the patient’s social life and have shown to decrease compliance and adherence to therapy. Additionally, as various topical treatments have been proven to be effective in treating AK, tolerability of local site reactions (LSRs) might drive the decision for appropriate treatment in an individual scenario. Therefore, we aimed to review prevalence of severe LSRs among various topical treatments for AK. In addition, we summarized discontinuation rates due to LSRs and possible therapy-unrelated risk factors for the development of LSRs with increased severity.
... The incidence of local skin reaction from ingenol mebutate gel treatment was even higher, with erythema in 97.5%, flaking/scaling in 96.3%, and crusting in 82.1% of the subjects throughout the treatment course. The intensity of local skin reaction was rated as moderate to severe in 56.7% at day 8 of ingenol mebutate gel treatment [34,37]. 5-FU cream also has an unfavorable side- effect profile which is unacceptable to many patients [38]. ...
Background:
Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects.
Objectives:
To evaluate the efficacy and safety of topical SR-T100 gel in treating AK.
Methods:
A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing.
Results:
123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR-T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100.
Conclusion:
The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK.
