5-Aminolaevulinic acid-based photodynamic therapy for actinic keratosis in Chinese patients: A prospective multicenter study

To the Editor: Actinic keratosis (AK) is a precancerous skin condition caused by chronic exposure to ultraviolet radiation. It mainly occurs on sun-exposed areas like the head and face, leading to cosmetic concerns and an increased risk of progressing to primary squamous cell carcinoma (with a 0.60% risk at 1 year and 2.57% risk at 4 years).1 Photodynamic therapy (PDT) is a targeted, non-invasive therapy that has been approved in Europe for the treatment of AK, squamous cell carcinoma in situ, and basal cell carcinomas. 5-Aminolaevulinic acid (ALA)-based PDT, which utilizes the photosensitizer ALA, has shown high cure rates, low recurrence rates, and favorable cosmetic outcomes as a first-line treatment for AK.1 However, due to variations in skin color, ethnicity, and lifestyle habits, the incidence of AK is lower among Asians compared to Caucasians.1 There are limited clinical studies on PDT for AK in Asia—particularly lacking large-scale multicenter trials. This knowledge gap hinders the establishment of treatment standards specifically tailored for Asian patients with AK undergoing PDT. Nevertheless, as the aging population increases in Asia, the incidence of AK demand for medical intervention among Asians is also rising accordingly. We conducted this multicenter study aiming to comprehensively investigate the efficacy and safety of ALA-PDT in Chinese patients with AK. The study was a prospective, multicenter clinical trial conducted in seven study centers in China (ChiCTR1800019213). It received approval from the Biomedical Research Ethics Committee of Peking University First Hospital (No. 2018.89), and each patient provided signed informed consent before participating. The patient inclusion criteria were: (1) age >18 years, (2) histopathologically diagnosed with AK. Exclusion criteria included: (1) patients requiring surgery, (2) patients with severe liver, kidney, heart disease, or immunodeficiency, (3) patients with a history of psychosis or epilepsy, (4) lactating or pregnant women, (5) patients with a history of skin photosensitivity, porphyria, or allergy to porphyrins, (6) patients deemed unsuitable for participation in this study for other reasons by the investigators, and (7) uncooperative patients unwilling to complete the follow-up. The size of each lesion was measured and recorded prior to treatment, followed by pretreating the lesions through removal of scales, crusts, and other inactive tissues to fully expose the fresh lesions. After pretreatment, the lesions were photographed again. ALA powder (Shanghai Fudan-Zhangjiang Biopharmaceutical Co., Ltd., Shanghai, China) was used to prepare fresh gel or solution (concentration 20%), and then was evenly applied to the AK lesions and extended 1.0 cm beyond the lesion boundary. The AK lesions were wrapped with plastic film and incubated for 3–4 h. Fluorescence photographs were taken using a hand-held light source (370–440 nm) after incubation. Then, the lesions were illuminated by 635 nm red LED light (Wuhan Yage Optic and Electronic Technique Co., Ltd., Wuhan, China), with a power density of 80–100 mW/cm2 and energy density of 80–120 J/cm2. A cold air device was used to relieve pain during illumination. After 7–14 days of PDT, patients were followed up to determine whether further treatment was necessary based on lesion remission. Up to six sessions of ALA-PDT could be provided for each patient. The efficacy of ALA-PDT for AK was evaluated at 3 months after the last treatment. Complete response was defined as lesions disappearing with only hyperpigmentation or hypopigmentation, based on clinical judgment. Lesion recurrence was examined at 6 months and 12 months after the last treatment, characterized by a new lesion confirmed through histopathology at the site of the original resolved lesion. At 12 months after the last treatment, physicians evaluated cosmetic outcomes and categorized them into four grades: (1) Excellent–slight erythema, or/and slight pigmented change compared to the surrounding skin, (2) Good–moderate erythema, or/and moderate pigmented change compared with the surrounding skin, (3) Moderate–mild or moderate scarring, atrophy, or sclerosis, and (4) Poor–extensive scarring, atrophy, or sclerosis. Additionally, patient satisfaction was assessed with an online/offline scale, which was divided into five levels: very dissatisfied, dissatisfied, generally satisfied, satisfied, and very satisfied. Adverse events (AEs) were recorded during treatment and follow-up. Patients assessed pain intensity at 3 min, 10 min after the treatment began, and 5 min after the completion of treatment by using the visual analog scale (VAS), ranging from 0 (no pain) to 10 (most intolerable pain). Statistical analyses were performed using the SAS 9.4 (SAS Institute Inc., Cary, USA). The relationship between relevant factors and efficacy was compared using chi-squared test. P-value 1 (2–4) 9 (81.8) 2 (18.2) By lesions Total 96 (96.0) 4 (4.0) Lesion location 1.0000 Trunk and limbs 2 (100.0) 0 Head, face and neck 94 (95.92) 4 (4.08) Lesion area (cm2) 0.8626 ≤1 50 (92.6) 4 (7.4) >1, (1.25–21.5) 43 (93.5) 3 (6.5) Totally, 63 and 68 patients were followed up at 6 months and 12 months, with no recurrence observed during both visits. After 12 months, physicians assessed the cosmetic effects and found that 76.5% (52/68) of patients had excellent cosmetic outcomes, while 23.5% (16/68) had good cosmetic outcomes. A total of 70 patients responded to the satisfaction scale, with proportions of very satisfied, satisfied, generally satisfied, dissatisfied, and very dissatisfied being 65.7% (46/70), 30.0% (21/70), 2.9% (2/70), 1.4% (1/70), and 0% (0/70), respectively. The patients who reported being generally satisfied and dissatisfied were those with incomplete response of lesions. Four types of adverse reactions, including pain, redness (55, 65.5%), itching (41, 48.8%), and scab formation (2, 2.4%), were observed during the study period. Most patients experienced mild-to-moderate pain. VAS scores showed that the highest VAS score was observed during the first treatment session. The average VAS scores were 4.51 ± 2.01 at 3 min after treatment began, 3.73 ± 1.83 at 10 min after treatment began, and 2.61 ± 1.64 at 5 min after completion of treatment, respectively. The pain was significant at the beginning of the treatment and then gradually decreased Supplementary Figure 3, https://links.lww.com/CM9/B893. Other AEs such as redness, itching, and crusting generally resolved spontaneously. No patients discontinued treatment because of AEs (including pain). No local or systemic photosensitive reactions was reported. Previous research suggested that differences in skin pigmentation may significantly affect light penetration during PDT and then affect the clinical efficacy of ALA-PDT in different populations of skin colors. The sample size of previous studies of ALA-PDT in Asian population (yellow race) is small. This study confirms that ALA-PDT is also an effective treatment for AK patients in China. However, further studies may be needed on the exact impact of skin color on efficacy. In this study, at 3 months after the last treatment with ALA-PDT, the patient complete response rate was 95.2%, and the lesion complete response rate was 96.0%. And no relapse was observed during the 6 months and 12 months of follow-up. These results exceeded those of previous studies, possibly due to increased ALA-PDT treatment sessions. In previous studies, AK patients were treated with 1 or 2 sessions of PDT, and the complete response rate was ≤85%.2–4 In this study, all patients received 3–5 sessions of ALA-PDT, with a complete response rate of 95.1% (78/82) at the 3-month follow-up for those who had received 3–4 sessions. Therefore, we believe that satisfactory results can be achieved in AK patients after undergoing 3–5 sessions of PDT. It is recommended to increase the number of PDT sessions if a patient does not achieve a complete response; however, the total number should generally not exceed six.1 The use of red light (wavelength 635 nm) as the illumination source may have also contributed to better treatment efficacy, since, red light penetrates deeper into tissues than blue light.5 The main adverse effect of ALA-PDT is pain. In this study, a cold air device was used throughout the ALA-PDT. We observed that the pain intensity initially increased and then decreased during the treatment process, with the highest level occurring 3 min after treatment began with the mean VAS score <5, indicating mild-to-moderate pain. In clinical practice, implementing relevant measures for pain relief at the beginning of PDT can effectively alleviate patients' discomfort and enhance their compliance and satisfaction. Photodynamic diagnosis (PDD), a novel non-invasive detection method, has been utilized for the boundary diagnosis of skin tumors, but with limited studies conducted on AK patients. Jeffes et al6 demonstrated an effective detection rate of 97% for AK lesions using PDD. This study clearly displayed the enrichment of ALA in AK lesions through fluorescence photography, confirming the precise targeting ability of ALA. Fluorescence-assisted diagnosis and guided treatment may emerge as future trends in diagnostics and treatment. However, further research and exploration are required. The limitation of the study is that it was a self-controlled study without a control group. In conclusion, this multicenter study suggests that a topical ALA-PDT regimen with 20% ALA, 3–4 h of incubation, and red light source treatment for 3–5 sessions lead to high complete response rates, favorable cosmetic effects, good patient tolerability, and minimal adverse reactions in Chinese AK patients. Importantly, the efficacy of ALA-PDT is not affected by lesion size, location, or number. Conflicts of interest None.