Summary
Background and Objectives
Solid organ transplant recipients have an increased risk of developing actinic keratosis. Recent studies show greater effectiveness when combining daylight photodynamic therapy with a posterior LED illumination for their treatment in immunocompetent patients. The aim of this study was to compare the effectiveness of combining daylight photodynamic therapy and LED illumination versus daylight photodynamic therapy alone for the treatment of actinic keratosis in solid organ transplant recipients.
Patients and Methods
This randomized intra‐patient study was conducted at University of Navarra Clinic. Solid organ transplant recipients with two 25 cm2 areas on the face or scalp with at least four actinic keratosis, were included. After receiving daylight photodynamic therapy in both areas, one of them was randomized to receive complementary LED illumination. The primary endpoint was the reduction of the baseline actinic keratosis at 3 months post‐treatment.
Results
Thirteen patients with a total of 169 AKs were recruited. At 12 weeks post‐treatment, the area treated with daylight and conventional photodynamic therapy showed a greater reduction in actinic keratoses (79.55% vs. 65.43%, p < 0.05).
Conclusions
Our results suggest greater effectiveness of combining daylight photodynamic therapy with LED illumination compared to daylight photodynamic therapy alone for the treatment of actinic keratosis in solid organ transplant recipients.
Keywords: actinic keratosis, Photodynamic therapy, solid organ transplant recipients
INTRODUCTION
Actinic keratosis (AK) are precancerous skin lesions caused by prolonged exposure to ultraviolet (UV) radiation, which clinically present as rough, hyperkeratotic brown‐red papules that primarily affect sun‐exposed areas like the face and the scalp. AK are considered evolving lesions as they can either regress, persist, recur, or progress into invasive squamous cell carcinoma (SCC). While the annual progression rate of AK to SCC in immunocompetent individuals is relatively low, ranging between 0% and 0.075% per lesion, this risk increases significantly in immunosuppressed patients, particularly solid organ transplant recipients (SOTRs), especially when they have numerous AKs or clinical signs chronic UV‐induced skin damage. 1 , 2 In fact, SOTRs with AK are 32 times more likely to develop SCC, which tends to be more aggressive, with a 5 to 10 times higher likelihood of metastasis and an increased risk of mortality. Therefore, early intervention is essential to prevent AK from evolving into SCC. 3 For this purpose, there are different topical therapies, such as photodynamic therapy (PDT), 5‐FU, or cryotherapy. Conventional photodynamic therapy (cPDT) is a well‐established treatment for AK that has demonstrate high efficacy and safety. 4 This procedure involves applying a photosensitizing agent – 5‐aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) – to the affected area, followed by exposure to a light source with a wavelength between 404 nm and 420 nm (blue light), or 635 nm (red light). This activation leads to the production of reactive oxygen species, as well as other indirect inflammatory and immunological processes, that result in tumor and precancerous cells death. 5 While most studies have focused on immunocompetent patients, a recent meta‐analysis confirmed its effectiveness in preventing and treating AK in transplant recipients as well. 6 However, a notable drawback of cPDT is the significant pain experienced during and after treatment, especially among transplant patients who often present a higher number of AK than immunocompetent individuals. 7 Given that PDT is one of the most effective treatments for AK, alternative approaches that reduce discomfort, such as daylight photodynamic therapy (dPDT), have been explored especially in immunocompetent patients. 8 DPDT not only offers field treatment but also improves patient comfort by reducing pain levels.
Numerous studies suggest that dPDT is therapeutically comparable to cPDT. Yet, there are only a few studies comparing both modalities in immunosuppressed patients. 6 , 9 However, it must be noted that in clinical practice, the promising results seen with dPDT may not always translate, particularly in immunosuppressed individuals. Consequently, there is a need to develop new PDT protocols that both enhance efficacy and improve patient tolerance. Recent research has demonstrated that combining dPDT and a posterior LED illumination (LED‐dPDT) could be more effective than dPDT alone for treating AK in immunocompetent patients, without compromising the treatment's safety or tolerability. 10 , 11 Therefore, we hypothesize that this treatment modality could also be effective in immunosuppressed patients, aiming to compare the effectiveness and tolerance of LED‐dPDT versus dPDT in treating AK in SOTRs.
PATIENTS AND METHODS
This prospective, randomized, comparative and intra‐patient study was conducted at the Department of Dermatology of University of Navarra Clinic from January 2023 to June 2024. The study was approved by the Local Ethics Committee of University of Navarra Clinic. We included consecutive patients evaluated in our department with at least two areas of 25 cm 2 with four AK lesions (I–III, Olsen) 8 or more in each in the face and/or scalp. To control intrapatient variability, participants were required to present two clinically comparable areas of photodamaged skin and AK. We excluded patients with prior treatments in the last 3 months, squamous cell carcinoma suspicion, patients with less than 5 years since transplantation or patients who declined treatment with PDT. Patient enrollment and AKs assessment using the Olsen scale were performed by the same dermatologist (R. S.‐V.) in all patients. Both informed consent and additional permission for publishing identifying information were obtained from all individual participants included in the study. Clinical variables such as gender, age, phototype, history of chronic photoexposure, personal history of skin cancer, allograft type and years of immunosuppression were collected. After patient recruitment, the areas were randomized at a 1 : 1 ratio using computer‐generated random numbers to determine which one would receive an additional LED illumination after daylight exposure, referred to as LED‐dPDT.
Photodynamic therapy protocol
Each patient received dPDT on the two 25 cm 2 treatment areas following the Spanish‐Portuguese consensus statement on dPDT. 12 Grade III AK were pre‐treated with curettage and MAL was applied evenly to both areas. Subsequently, illumination was performed with a red‐light source (10 min, 37 J/cm2, BF‐RhodoLED®) immediately after 2 h of sun exposure by a different dermatologist (I. O.‐R.). The same protocol was repeated after 2 weeks for each area. Pictures of all treatment sites were taken at baseline and 12 weeks after treatment. All dPDT sessions were performed under optimal weather conditions (range 16–26°C).
Evaluation of clinical effectiveness and safety
The evaluation of the effectiveness of the treatments was based on clinical response. At baseline and at a clinical follow‐up visit 3 months after PDT, AK were mapped, counted, and graded, as proposed by Olsen et al. 13 , by a blinded dermatologist (R. S.‐V.). Treatment areas and AK lesions were marked with a grid. The reduction in the number of AK lesions was established as the primary efficacy endpoint and defined as the percentage of individual lesions cleared at the respective site of the patient 12 weeks after both treatment options. Secondary endpoints included complete response (CR) and partial response (PR) rates, defined as the reduction in the 100% or the ≥ 75% of the basal AK lesions, respectively.
Local skin response (LSR) 14 was also assessed 48 h after the treatment using a 24‐point scale which included different factors (erythema, scaling, crusting, swelling, vesiculation, and ulceration). Pain was assessed by the patient after both treatments on a 10‐point Visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst pain patient can imagine). In addition, patients were questioned about their overall preferred treatment protocol.
Statistical analysis
Data was collated in an Excel spreadsheet and imported into StataTM (StataCorp. 2003. Stata Statistical Software: Release 8.0., College Station, TX, U.S.A. Stata Corporation) for analysis. Continuous data were expressed as mean standard deviations and compared with U Mann Whitney's tests. Fisher's exact test was performed to compare proportions. The results were defined as statistically significant with p values p < 0.05. A Spearman's correlation test was run to determine the relationship between LSR and the reduction of AK. To determine the sample size, we calculated that 160 AK lesions would provide the study with 80% power, with an alpha error of 5% and a beta error of 20%, assuming a 20% of difference in response rates between the two groups based on the results of previous studies conducted in immunocompetent patients.
RESULTS
A total of 13 male patients aged 49 to 87 years‐old (mean 69.2) with 169 clinically confirmed AK lesions were included in this study. 53% of the patients had a phototype III followed by phototypes I and II (46.2%). 69.2% of the patients showed chronic sun exposure throughout working life, and 69.2% showed a skin cancer medical history (Table 1). AK at baseline did not show significant differences in number and clinical grade between randomized areas (Table 2). At 12 weeks post‐treatment, the area treated with LED‐dPDT showed a greater reduction in baseline AKs compared to the area treated with dPDT (79.6% vs. 65.4%, p < 0.05) (Figure 1). Additionally, CR (15.4% vs. 7.7%, p > 0.05) and PR (61.5% vs. 38.5%, p > 0.05) rates were higher in the areas treated with LED‐dPDT, although the results did not show statistically significant differences (Table 3). Areas treated with LED‐dPDT showed higher LSRs (4.6 ± 2.1 vs. 3.9 ± 1.7) and a low increase in pain during illumination when compared to dPDT (VAS: 2.1 vs. 0.1, p < 0.05) (Table 4). However, patients’ satisfaction was rated as very good or good in 92.3% of the patients. 84.6% of them had no particular preference for either treatment. We also observed a linear correlation between the score of LSR and the percentage of reduced AK lesions 12 weeks after treatment (Spearman correlation coefficient, r = 0.35; p = 0.004).
TABLE 1.
Baseline patient characteristics.
| Baseline patient characteristics (n = 13) | |
|---|---|
| Sex | |
| Male | 13 (100%) |
| Female | 0 (0%) |
| Age in years, mean (SD) | 69.2 (7.7) |
| Fitzpatrick skin phototype | |
| II | 6 (46.2%) |
| III | 7 (53.8%) |
| Chronic solar exposure | |
| Yes | 9 (69.2%) |
| No | 5 (38.5%) |
| Skin cancer history | |
| No | 4 (30.8%) |
| Non‐melanoma skin cancer | 9 (69.2%) |
| Melanoma | 0 (0%) |
| Years of immunosuppression, mean (SD) | 13.1(6.9) |
| Allograft type | |
| Kidney | 8 (61.5%) |
| Heart | 4 (30.8%) |
| Liver | 1 (7.7%) |
Abbr.: SD, standard deviation
TABLE 2.
Actinic keratosis characteristics at basal visit according to treatment areas.
| dPDT | LED‐dPDT | ||||
|---|---|---|---|---|---|
| AK basal count | n | Mean (SD) | n | Mean (SD) | p value |
| Total | 81 | 6.2 (1.2) | 88 | 6.8 (1.1) | NS |
| AK grade I | 38 | 2.9 (1.8) | 42 | 3.2 (1.7) | NS |
| QA grade II | 35 | 2.7 (1.3) | 36 | 2.8 (1.6) | NS |
| QA grade III | 8 | 0.6 (0.9) | 10 | 0.8 (0.9) | NS |
Abbr.: LED‐dPDT, combination of daylight photodynamic therapy and LED illumination; dPDT, daylight photodynamic therapy; NS, non‐significant; SD, standard deviation
FIGURE 1.
(a, c) Clinical images at baseline and 3 months after treatment with (b) dPDT and (d) LED‐dPDT.
TABLE 3.
Effectiveness of LED‐dPDT and dPDT according to treatment areas.
| Clinical response (week 12) | dPDT | LED‐dPDT | |||
|---|---|---|---|---|---|
| n | % | n | % | p value | |
| CR | 1 | 7.7% | 2 | 15.4% | 1 * |
| PR | 5 | 38.5% | 8 | 61.5% | 0.43 * |
| AK count decrease | 53/81 | 65.4% | 70/88 | 79.6% | 0.005 ** |
| AK grade I | 21/38 | 55.3% | 30/42 | 66.7% | 0.16 ** |
| AK grade II | 26/35 | 74.3% | 31/36 | 86.1% | 0.37 ** |
| AK grade III | 6/8 | 75% | 9/10 | 90% | 0.44 ** |
Abbr.: AK, actinic keratosis; LED‐dPDT, combination of daylight photodynamic therapy and LED illumination; CR, complete response; dPDT, daylight photodynamic therapy; PR, partial response; SD, standard deviation
Fisher's exact test for 2 × 2 contingency tables
Mann‐Whitney U‐Test
TABLE 4.
Safety data of LED‐dPDT and dPDT according to treatment areas.
| Local skin reaction (LSR) | dPDT Mean (SD) | LED‐dPDT Mean (SD) | p value |
|---|---|---|---|
| Total LSR | 3.9 (1.7) | 4.6 (2.1) | 0.24 ** |
| Erythema | 1.3 (0.5) | 1.6 (0.5) | 0.18 ** |
| Edema | 1.9 (0.31) | 1.9 (0.3) | 1 ** |
| Flaking/scaling | 1 (0.5) | 1.1(0.6) | 0.65 ** |
| Crusting | 0 | 0.1 (0.3) | 0.31 ** |
| Erosion/ulceration | 0.1 (0.3) | 0.4 (0.5) | 0.13 ** |
| Vesiculation/pustulation | 0 | 0 | |
| VAS | 0.1 (0.3) | 2.08 (0.9) | <0.05 ** |
Abbr.: LED‐dPDT, combination of dalight photodynamic therapy and LED illumination; dPDT, daylight photodynamic therapy; SD, standard deviation; VAS, visual analog scale
Mann‐Whitney U‐Test
DISCUSSION
Treatment of extensive fields cancerizations and AKs in SOTR, generally located on the face and scalp, is essential for preventing non‐melanoma skin cancer in these high‐risk patients but presents a significant challenge in clinical practice. To date, cPDT is the most extensively studied treatment for both preventing 15 and treating 16 AK in SOTR, offering the highest complete response rates (50% 9 to 89% 17 ), particularly with two cycles of PDT. However, one of its main drawbacks is the pain experienced during and after each session, which may be even more pronounced in transplant recipients due to their larger areas of field cancerization compared to immunocompetent patients.
As a result, dPDT, which uses daylight to activate the photosensitizer, is often used as an alternative since it is generally better tolerated and shows similar effectiveness in immunocompetent patients. 8
Daylight‐PDT is recognized in clinical guidelines as a recommended treatment for immunocompromised patients with single or multiple AKs and field cancerization. 18 However, in this group of patients response rates are generally lower, 9 likely due to their weakened immune system, which could diminish their overall responsiveness to these therapies. Despite limited data on its efficacy in SOTRs, dPDT remains a viable option, although studies suggest lower complete response rates compared to cPDT (46% 9 vs. 78% 19 ) in this population.
For this reason, while dPDT is often preferred for its better tolerability, especially in patients who experience significant discomfort with cPDT, it may not always be enough on its own. Hence, some studies have explored the combination of different treatments, such as laser therapy, prior to applying the photosensitizer to improve efficacy. 9 Furthermore, recent studies suggest that combining dPDT with an additional session of LED illumination could enhance the effectiveness of dPDT without negatively impacting its overall tolerability. 10 , 11
The effectiveness observed in these previous studies aligns with the findings from our study in immunosuppressed patients. This increase in effectiveness could be attributed to the residual protoporphyrins remaining after dPDT in some patients, which may be activated during the additional LED illumination phase. 10 Moreover, it should also be noted that the persistence of protoporphyrins might result from a variability in light exposure depending on weather conditions or patient adherence to the recommended exposure times, which may lead to a lower percentage of red light exposure in some circumstances. For this reason, the application of LED lamps could be particularly beneficial as red light penetrates more effectively into deeper tissues, enhancing a cytotoxic effect in deeper layers. 20 Additionally, this deeper penetration may promote an immunomodulatory response and activate inflammatory and immunological processes which may enhance treatment response. 5 , 21
In our study, the CR rates for LED‐dPDT of the whole area for LED‐dPDT were low (15.4%), which could be attributed to the higher grade and number of AKs in immunosuppressed patients, as well as the small sample size of the study. However, when examining the reduction in the number of baseline AK lesions, LED‐dPDT achieved a 79.6% reduction, comparable to the results from studies that used cPDT in SOTR (78%–89%) 17 , 19 and higher than results from studies using dPDT (46%). 9 These differences highlight the view held by some authors that CR is not an ideal primary variable in AK studies, and that lesion clearance rates may be a more reliable measure of treatment efficacy. 22 Interestingly, our results show that the sites treated with LED‐dPDT had a greater reduction of baseline AK lesions compared to those treated with dPDT, particularly for grade III AK. This result shows a limitation in our study, as we did not check individually the resolution of every lesion. This means that grade III AK may have diminished grades after the treatment, leading to a lower number of grade III AK at follow‐up.
In addition, it must be taken into account that in our study the reduction of AK was less than was observed in previous studies involving immunocompetent patients treated with LED‐dPDT (87.2%). 10 However, this outcome was anticipated as immunosuppressed individuals generally exhibit greater resistance to treatment and a lower inflammatory response, which could be observed as patients presented lower LSR than immunocompetent individuals (4.6 vs. 6.4). 10 This positive correlation between efficacy and local reactions has been observed by other researchers and supports the hypothesis that local reactions could be a predictor of clinical response. 23 In our study we also found a moderate correlation between the LSR and the percentage of reduction in AK at the 3‐month follow‐up (p < 0.05).
Regarding tolerability, our findings show that patients exhibited a high level of tolerance to LED‐dPDT treatment. The LSR was slightly greater in the LED‐dPDT group; however, the overall levels remained low (4.6/24) and did not present statistically significant differences when compared to dPDT (3.9 vs. 4.6). Clinically, no instances of poor tolerance were observed, as the VAS ratings were minimally elevated in patients treated with the lamp (2.1). Furthermore, no adjustments to lamp intensity were necessary, and treatment interruptions were not required. Notably, only two patients expressed a preference for dPDT, which was not attributed to adverse tolerance but rather the need for hospital return following the dPDT procedure.
Study limitations include the small sample size and the fact that it is a single‐center study which may affect the generalizability of the results. Additionally, during the follow‐up period, only the total number of AK was evaluated, without assessing whether individual lesions had completely resolved. This approach may have led to an apparent greater reduction in higher‐grade AK, as the severity of some lesions may have been diminished, resulting in their being counted as lower‐grade AK instead. Finally, the lack of long‐term follow‐up data limits our ability to assess the durability of the treatment outcomes overtime.
In conclusion, our findings suggest that LED‐dPDT enhances treatment effectiveness in SOTRs, who often present with extensive fields of cancerization and refractory AKs, without compromising tolerability. However, more controlled studies are necessary to gather more accurate data on efficacy and safety in this hard‐to‐treat population.
CONFLICT OF INTEREST STATEMENT
None.
ACKNOWLEDGEMENTS
Open access funding enabled and organized by Projekt DEAL.
Oteiza‐Rius I, Morelló‐Vicente A, Aguado‐Gil L, et al. Combination of LED illumination and daylight photodynamic therapy for the treatment of actinic keratosis in solid organ transplant recipients: a prospective, randomized, comparative, intra‐patient study. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2025;23:713–718. 10.1111/ddg.15665
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