Neoadjuvant Photodynamic Therapy: An Updated Therapeutic Approach for Non-Melanoma Skin Cancers.

OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.

Treatment Outcomes of Adjunct and Stand-alone Photodynamic Therapy in Patients With Extramammary Paget Disease: A Literature Review.

BACKGROUND: Extramammary Paget disease (EMPD) is a rare malignant neoplasm arising from apocrine gland-bearing skin. The surgical management of EMPD is often coupled with noninvasive techniques including cryotherapy, ablative lasers, topical chemotherapies, and photodynamic therapy (PDT). The specificity and preservation of tissue that PDT with photosensitizers 5-aminolevulinic acid or 5-methyl aminolevulinate allows makes it a potential treatment of EMPD. METHODS: The authors present a review of 13 studies, from 2002 to 2019, examining the reported efficacy of PDT alone and adjunctive PDT in EMPD treatment. RESULTS: In the 52 patients with 56 lesions who received stand-alone PDT, 20 lesions (35.7%, n = 20/56) experienced complete resolution, 31 lesions (55.4%, n = 31/56) experienced partial resolution, 5 lesions (8.9%, n = 5/56) failed to demonstrate response to treatment, and 23 lesions (41.1%, n = 23/56) had recurrence. In the 56 patients with 66 lesions that received adjunctive PDT paired with surgery ( n = 55/66), imiquimod ( n = 4/66), holmium laser and surgery ( n = 1/66), Mohs surgery ( n = 2/66), and combined surgery, imiquimod, and 5-fluorouracil ( n = 1/66), 34 lesions (51.5%) experienced complete resolution, 27 lesions (40.9%) experienced partial resolution, 5 lesions (7.6%) failed to demonstrate any response to treatment, and 16 lesions (24.2%) had EMPD recurrence. CONCLUSION: Further studies with larger sample size are needed to consolidate these findings and inform clinical decisions.

The quantitative analysis of low-concentration (2%) ALA-PDT assisted with Q-switch 1064-nm Nd:YAG laser for acne vulgaris treatment.

Conventional 5-aminolevulinic acid-photodynamic (ALA-PDT) therapy (10-20%) has been widely applied for moderate-to-severe acne. The aim of this study is to investigate the effects of non-ablative Q-switched 1064-nm Nd:YAG laser-assisted ALA-PDT with low concentration (2%) on the treatment of acne vulgaris. Enrolled patients were randomly assigned to 2 groups. One group received combined therapy of 2% ALA-PDT and non-ablative Q-switched 1064-nm Nd:YAG laser, and the other received only 2% ALA-PDT. Patients in each group had received 3-session treatments with 4-week intervals (week 0, 4, and 8). Sebum secretion, melanin index, erythema index, and transepidermal water loss (TEWL) were assessed at week 2, 8, 12, and 24. VISIA® skin image system score and global esthetic improvement scale (GAIS) were also evaluated. Twenty-four participants were enrolled and evenly randomized to two groups. Significant improvement in sebum secretion was noted in combined therapy group compared to the monotherapy group at week 12 (37.5% versus 16.3%), and the improvement would still be noted until week 24 (18.3% versus 17.4%). Combined group also showed more severe melanin index and erythema index after treatment. For VISIA® skin analysis, patients in combined group had better percentile ranking in porphyrins and red-light images. There were no significant differences in GAIS at the end of the follow-up between each group, whereas higher proportion of satisfaction was noted in combined group at week 2. With the assistance of laser, low concentrations (2%) of 5-ALA can provide effective phototoxic reactions in treating acne vulgaris. The satisfaction of patients is high with acceptable adverse effects.

Daylight-PDT: everything under the sun.

5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) was first implemented over three decades ago and has since been mainly part of clinical practice for the management of pre-cancerous and cancerous skin lesions. Photodynamic therapy relies on the combination of a photosensitizer, light and oxygen to cause photo-oxidative damage of cellular components. 5-Aminolevulinic acid (ALA) is a natural precursor of the heme biosynthetic pathway, which when exogenously administered leads to the accumulation of the photoactivatable protoporphyrin IX. Although, effective and providing excellent cosmetic outcomes, its use has been restricted by the burning, stinging, and prickling sensation associated with treatment, as well as cutaneous adverse reactions that may be induced. Despite intense research in the realm of drug delivery, pain moderation, and light delivery, a novel protocol design using sunlight has led to some of the best results in terms of treatment response and patient satisfaction. Daylight PDT is the protocol of choice for the management of treatment of multiple or confluent actinic keratoses (AK) skin lesions. This review aims to revisit the photophysical, physicochemical and biological characteristics of ALA-PDT, and the underlying mechanisms resulting in daylight PDT efficiency and limitations.

Measurements of illuminance in simulated daylight photodynamic therapy.

BACKGROUND: Simulated daylight photodynamic therapy (SDL-PDT) is a new treatment alternative for actinic keratosis. The aim of this study was to show how the illuminance that reaches the target skin area during SDL-PDT depends on the spatial positioning of the patient. METHODS: In this technical validation study, illuminance from the SDL-PDT system IndoorLux© was measured at different angles, directions, and distances from the light sources corresponding to potential target skin areas. Using two different photometers, data from 63 measuring points at seven specific distances from the ceiling were collected at 0°, 45°, and 90° angles, respectively. Illuminance levels ≥12,000 lux were regarded as adequate. Hotspots were defined as adequate measurements in all directions at a specific measuring point at distances of 1.3, 1.5, and 1.8 m from the light sources (i.e., the most common patient treatment positions). RESULTS: Adequate illuminance levels were more common with photometer 1 (73%) than photometer 2 (57%). Almost all illuminance levels were adequate at a 0° angle with both photometers. Adequate illuminance levels were observed at 82-93% of the measuring points at a 45° angle and 22-47% at a 90° angle. Hotspots were registered with both photometers at all measuring points at 0°; 59-79% of the measuring points at 45°; and 0-21% at 90°. CONCLUSION: Patient positioning is important during SDL-PDT. Adequate illuminance is achieved if target skin areas are positioned at 0°-45° angles relative to the light sources, but not at 90° angles.

Combined therapy of 5-aminolevulinic acid photodynamic therapy and intense pulsed light for rosacea.

Rosacea is difficult to treat. Therefore, new alternative modalities are necessary to demonstrate. The present study was conducted to assess the efficacy and safety of the combined therapy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and intense pulsed light (IPL) for rosacea to provide a new treatment option for rosacea. The study was conducted from November 2017 to April 2019 at the Department of Dermatology, The First Hospital of China Medical University. Patients aged 18-65 years and diagnosed clinically as erythematotelangiectatic (ET) or papulopustular (PP) rosacea were enrolled. Three times of ALA-PDT at 10 days interval followed by 3 times of IPL at 3-4 weeks interval were defined as 1 session and applied to the whole face of each patient. ALA-PDT: 5% ALA, red light (fluency dose 60-100 mW/cm2, 20 min); IPL: 560/590/640 nm, double/triple-pulse mode, pulse width 3.0 to 4.5 ms, delay time 30-40 ms, energy fluency 14-17 J/cm2. Ten patients were enrolled in the study. Among them, 4 patients received only 1 session, while 6 patients received 2 sessions. After all treatments, 50% of patients achieved 75-100% improvement, and 30% achieved 50-75% improvement. Forty percent of patients were graded very satisfaction and 30% graded moderate satisfaction. All noninvasive measurements showed no significant differences among all time points (p > 0.05). The side effects were pain, burning sensation, itching, erythema, desquamation, slight edema, slight exudation, and hyperpigmentation. All of which were tolerable and recovered in a few days. The combined therapy of ALA-PDT and IPL showed an effective option for rosacea with a safety profile.

Skin field cancerisation: A systematic review of the literature regarding its treatment.

INTRODUCTION: Skin neoplasms are the most frequent malignant lesions, increasing patient's morbidity when associated with skin field cancerisation. There is a need to understand the current therapies, both clinical and surgical. METHODS: A systematic review was performed according to the PRISMA guideline, registered in PROSPERO: CRD42018114826, including studies from 2012 to 2019. RESULTS: Seven hundred and eighty-two studies were found, of which 21 were included. Of these, 8 primary studies were randomised controlled trials: fractional CO2 laser-assisted photodynamic therapy (PDT) vs. PDT (no significance), daylight PDT vs. PDT (no significance, daylight PDT had less adverse effects), trichloroacetic acid peel vs. 5-aminolaevulinic acid PDT (clinical improvement of aminolaevulinic acid PDT), 5-Fluorouracil 0.5%/Salicylic Acid 10% vs. vehicle (clinical improvement of 5-Fluorouracil 0.5%/Salicylic Acid 10%), photolyase vs. sun filters (no significance), sunscreens vs. sunscreens plus DNA repair enzymes (DNA Repair Enzymes was more effective in reducing field cancerisation). Only one systematic review was included in which there was effectiveness of daylight PDT in the treatment of actinic keratoses. The other 12 included studies had a lower level of evidence including surgical studies. CONCLUSION: Clinical studies are more relevant in the treatment of the field cancerisation. There is a lack of surgical studies.

Aminolevulinic Acid 20% Solution Combined With Photodynamic Therapy for Treatment of Actinic Keratoses: A Review.

Actinic keratoses (AK) are lesions with potential to transform into nonmelanoma skin cancers. Numerous methods are available for treatment of AK. Here, we review clinical trial data on the use of photodynamic treatment combined with the sensitizing agent aminolevulinic acid 20% solution (ALA-PDT) for AK management. Although treatment guidelines for AK vary in their specific recommendations, efficacy of ALA-PDT is considered comparable or better relative to other FDA-approved treatments for AK. It is generally well tolerated and has a very acceptable long-term safety profile. ALA-PDT is typically recommended for patients who have multiple AKs and is associated with improved cosmetic outcomes compared with cryotherapy. Patients who undergo treatment with ALA-PDT should receive thorough education regarding the risks and benefits of treatment, the treatment regimen and the importance of adhering to it, how to manage local reactions, and signs and symptoms that warrant further evaluation. J Drugs Dermatol. 2021;20(11):1239-1244. doi:10.36849/JDD.6166.

The application of physical pretreatment in photodynamic therapy for skin diseases.

Photodynamic therapy (PDT) is widely used in skin diseases; the response rate of PDT treatment varies widely. The limited penetration in the tissue of photosensitizers influenced the penetration depth of PDT, which obviously impacts the therapeutic effect. The studies have improved the efficacy of PDT through various pretreatment applications; especially, the physical pretreatment had achieved significant outcomes. We will review the physical pretreatment to optimize the efficacy of PDT in skin diseases by searching the literature on this topic. The types of physical pretreatment commonly used in the clinical practice are discussed: curettage, superficial shaving, laser, surgical resection, plum-blossom needles, and microneedles. Compared with PDT alone, the physical pretreatment before PDT application was generally improved the efficacy and reduced the recurrence, especially in actinic keratoses (AK), Bowen disease (BD), basal cell carcinoma (BCC), and viral warts. The application of the physical pretreatments before PDT may improve the efficacy of PDT in various skin diseases. However, each kind of physical pretreatment has the benefit and shortcoming, and the applicable situation is different.

Excision combined with photodynamic therapy for scrotal Paget's disease in patients aged over 60 years.

OBJECTIVE: To investigate the safety and efficacy of wide local excision combined with aminolevulinic acid (ALA) photodynamic therapy (PDT) for the treatment of scrotal Paget's disease in patients of advanced age. METHODS: Data were collected for 16 patients (mean age, 68.44 years) with scrotal Paget's disease treated with wide local excision combined with ALA PDT and followed up from June 2014 to February 2018. Pathological examination after wide local excision confirmed Paget's disease. The patients underwent three courses of ALA PDT postoperatively and were followed up to determine the curative effect and complications in the short and middle term. RESULTS: The disease duration ranged from 4 to 76 months (mean, 36 months). Ten patients underwent simple excision, six underwent skin flap transfer, and two required reoperations due to skin flap necrosis and infection. The patients were followed up for 3 to 42 months after ALA PDT, during which time two patients developed metastasis (recurrence rate, 12.50%). No other serious complications occurred during follow-up except for lower limb movement disorder in one patient (6.25%). CONCLUSIONS: Wide local excision combined with ALA PDT shows good clinical efficacy and a low complication rate in patients of advanced age with scrotal Paget's disease.

Italian expert consensus paper on the management of patients with actinic keratoses.

Two round tables involving experts were organized in order to reach a consensus on the management of patients with actinic keratosis (AK). In the first, seven clinical questions were selected and analyzed by a systematic literature review, using a Population, Intervention, Control, and Outcomes framework; in the second, the experts discussed relevant evidences and a consensus statement for each question was developed. Consensus was reached among experts on how to best treat AK patients with respect to different clinical scenarios and special populations. Lesion-directed treatments are preferred in patients with few AKs. Patients with multiple AKs are challenging, with more than one treatment usually needed to achieve complete lesion clearance or a high lesion response rate, therapy should be personalized, based on previous treatments, patient, and lesion characteristics. Methyl aminolevulinate-PDT, DL (day light) PDT, and imiquimod cream were demonstrated to have the lowest percentage of new AKs after post treatment follow-up. For IMQ 5% and 3.75%, a higher intensity of skin reactions is associated with higher efficacy. Photodynamic therapy (PDT) is the most studied treatment for AKs on the arms. Regular sunscreen use helps preventing new AKs. Oral nicotinamide 500 mg twice daily, systemic retinoids and regular sunscreen use were demonstrated to reduce the number of new squamous cell carcinomas in patients with AKs. Limited evidence is available for the treatment of AKs in organ transplant recipients. There is no evidence in favor or against the use of any of the available treatments in patients suffering from hematological cancer.

Split-Sided Chest Study of Skin Rejuvenation Comparing Low-Energy, 1,927-nm Thulium Fractional Laser Treatment Prior to Photodynamic Therapy Versus Photodynamic Therapy Alone.

BACKGROUND AND OBJECTIVES: Treatment of photoaging and intrinsic aging of the chest, with the associated concerns of skin roughness, uneven pigmentation, laxity, atrophy, and telangiectasias, can be problematic because of the potential for worsened esthetic outcomes with existing treatments. This study assessed the efficacy and safety of using nonablative fractional laser therapy (FLT) pretreatment with photodynamic therapy (PDT) versus PDT alone for chest rejuvenation. STUDY DESIGN/MATERIALS AND METHODS: In a randomized, evaluator-blinded, split-sided study, adult female patients with photodamage to the chest received three treatment courses over an 8-week period with follow-up visits at Weeks 12 and 20. FLT was applied to one side of the chest, randomly assigned at baseline, followed by aminolevulinic acid-based PDT, delivered using a thermal, short incubation, broad area technique, to both sides of the chest. In-person and photographic assessments were conducted using five-point scales to evaluate outcomes including rhytides, pigmentation, skin texture, and telangiectasias. RESULTS: Eleven adults completed the study, of whom 11 had improved scores for rhytides and 10 had improved scores for skin texture at Week 20. There was no significant difference in any efficacy outcome between FLT and PDT and standard PDT alone. The severity of adverse events was rated significantly greater with the combined FLT-PDT treatment vs PDT alone. CONCLUSIONS: Significant improvements were observed vs baseline for both sides of the chest treated with FLT-PDT or standard PDT following three treatment sessions. No significant difference in efficacy was observed between treatment approaches, although adverse events were more severe on the FLT-pretreated side. This study was not registered as it qualified as a nonsignificant risk study. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial.

BACKGROUND: Organ transplant recipients (OTR) have a higher risk of actinic keratosis (AK) and keratinocyte carcinomas (KC). There are no clinical trials assessing the effectiveness of daylight photodynamic therapy (DPDT) to prevent new AK and KC in OTR. OBJECTIVES: To determine whether repeated treatments of field cancerization with DPDT are effective in preventing new AK and KC in OTR. METHODS: A randomized, intra-subject controlled, evaluator-blind, split-face and/or scalp trial, from April 2016 to October 2018. Participants were OTR older than 18 years, 1-year posttransplant, with at least 5 AK on each hemi-face/hemi-scalp. One side received six field treatments with DPDT: two sessions 15 days apart at baseline, two at 3 months and two at 9 months after baseline. Control side received lesion-directed treatment with cryotherapy (double freeze-thaw) at baseline, 3 and 9 months. Total number of lesions (AK and KC) at 21 months, number of new AK and KC at 3, 9, 15 and 21 months and treatment preferences were analysed. RESULTS: Of 24 men included, 23 were analysed at 3 months; and 21, at 9, 15 and 21 months. Mean (SD) age was 69.8 years (9.2). The total number of lesions at 21 months was 4.7 (4.3) for DPDT and 5.8 (5.0) for control side; P = 0.09. DPDT showed significantly lower means [SD] of new lesions compared to control side at 3 months (4.2 [3.4] vs. 6.8 [4.8]; P < 0.001), 9 months (3.0 [3.3] vs. 4.3 [3.4]; P = 0.04) and 15 months (3.0 [4.6] vs. 4.8 [5.0]; P = 0.02), and non-significant at 21 months (3.7 [3.5] vs. 5.0 [4.5]; P = 0.06). Most participants preferred DPDT. CONCLUSION: DPDT showed potential effectiveness in preventing new AK and KC in OTR by consecutive treatments of field cancerization. The preference for DPDT could facilitate adherence to the long-term treatment necessary in these patients.

Daylight photodynamic therapy with methyl aminolevulinate cream is as effective as conventional photodynamic therapy with blue light in the treatment of actinic keratosis: a controlled randomized intra-individual study.

BACKGROUND: We know the efficacy of daylight phototherapy dynamic (DL-PDT) in the treatment of actinic keratosis (AK). But the almost studies have compared daylight with red light using methyl aminolevulinate cream and not with blue light. PDT with blue light is another conventional PDT that is effective in the treatment of AKs. OBJECTIVES: The aim of this study is to assess the efficacy and the safety of DL-PDT vs. PDT in blue light in the treatment of AKs. METHODS: This randomized, controlled, intra-individual efficacy and safety study enrolled 26 subjects. AKs on the face/scalp were treated once, with DL-PDT on one side and c-PDT on the contralateral side. Primary endpoints for DL-PDT at week 12 were efficacy with clearance of AKs and safety with assessment of pain. Lesions with complete response 12 weeks after one treatment session were followed until week 24. RESULTS: More than 1000 AK were studied. At week 12, the raw number of disappeared AK lesions at 3-month follow-up was 19.6 (±6.0) for DL-PDT and 20.0 (±6.9) for c-PDT with P = 0.8460 (90.5% vs. 94.2% of AK disappearance, respectively). The response was maintained at 6 months (90.0% and 94.6% of AK reduction, respectively). DL-PDT was nearly painless than c-PDT with light blue: 1.2 vs. 5.1, respectively (P < 0.0001). CONCLUSIONS: Daylight-PDT seems as effective as c-PDT with light blue and DL-PDT is less painful. The response of DL-PDT was sustainable until 6 months.

Comparison of 10 efficient protocols for photodynamic therapy of actinic keratosis: How relevant are effective light dose and local damage in predicting the complete response rate at 3 months?

BACKGROUND: Topical photodynamic therapy is an established treatment modality for various dermatological conditions, including actinic keratosis. In Europe, the approved protocols for photodynamic therapy of actinic keratosis involve irradiation with either an Aktilite CL 128 lamp or daylight, whereas irradiation with the Blu-U illuminator is approved in the United States. Many other protocols using irradiation by a variety of light sources are also clinically efficient. OBJECTIVES: This paper aims to compare 10 different protocols with clinically proven efficacy for photodynamic therapy of actinic keratosis and the available spectral irradiance of the light source. Effective irradiance, effective light dose, and local damage are compared. We also investigate whether there is an association between the complete response rate at 3 months and the effective light dose or local damage. METHODS: The effective irradiance, also referred to as protoporphyrin IX-weighted irradiance, is obtained by integrating the spectral irradiance weighted by the normalized absorption spectrum of protoporphyrin IX over the wavelength. Integrating the effective irradiance over the irradiation time yields the effective light dose, which is also known as the protoporphyrin IX-weighted light dose. Local damage, defined as the total cumulative singlet oxygen molecules produced during treatment, is estimated using mathematical modeling of the photodynamic therapy process. This modeling is based on an iterative procedure taking into account the spatial and temporal variations in the protoporphyrin IX absorption spectrum during treatment. RESULTS: The protocol for daylight photodynamic therapy on a clear sunny day, the protocol for daylight photodynamic therapy on an overcast day, the photodynamic therapy protocol for a white LED lamp for operating rooms and the photodynamic therapy protocol for the Blu-U illuminator perform better than the six other protocols-all involving red light illumination-in terms of both effective light dose and local damage. However, no association between the complete response rate at 3 months and the effective light dose or local damage was found. CONCLUSIONS: Protocols that achieve high complete response rates at 3 months and low pain scores should be preferred regardless of the effective light dose and local damage. Lasers Surg. Med. 50:576-589, 2018. © 2018 Wiley Periodicals, Inc.