Comparative tolerability and efficacy of daylight, conventional, and combination aminolevulinic acid photodynamic therapy for treatment of actinic keratosis

To the Editor: The drawbacks to photodynamic therapy (PDT) for actinic keratoses (AK) include pain during illumination and patient access to a light source that is approved by the US Food and Drug Administration. To address this, dermatologists are exploring daylight PDT.1Wiegell S.R. Haedersdal M. Philipsen P.A. et al.Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study.Br J Dermatol. 2008; 158: 740-746Crossref PubMed Scopus (260) Google Scholar Clinical studies in Europe and South America provide initial evidence that daylight exposure is efficacious.2Rubel D.M. Spelman L. Murrell D.F. et al.Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.Br J Dermatol. 2014; 171: 1164-1171Crossref PubMed Scopus (160) Google Scholar,3Grinblat B. Galimberti G. Pantoja G. et al.Feasibility of daylight-mediated photodynamic therapy for actinic keratosis throughout the year in Central and South America: a meteorological study.Int J Dermatol. 2016; 55: e488-e493Crossref PubMed Scopus (9) Google Scholar This randomized, single-blind trial investigated the tolerability and safety of daylight PDT for AK on the face and scalp in Northern California. Participants with 4 to 20 face/scalp AKs were randomly selected (1:1:1) to 3 treatment groups (NCT03322293). Patients underwent topical application of aminolevulinic acid HCl (ALA) solution 20%. Group A had conventional treatment of 1 hour of incubation and 16 minutes, 40 seconds of 417-nm Blue Light Photodynamic Therapy (BLU-U; Sun Pharmaceutical Industries, Inc.). Group B received combination therapy of 15 minutes of incubation, 16 minutes 40 seconds BLU-U, and 45 minutes of daylight. Group C received daylight therapy of 15 minutes of incubation and 1 hour of daylight (supplemental Fig 1; available at https://doi.org/10.17632/rccd7rb8yp.1). Irradiance was measured with a spectroradiometer. The primary endpoint was tolerability, measured by patient-reported pain and blinded assessment of local skin reaction (LSR). Safety endpoints were (1) any adverse event (AE), (2) 1 or more serious AEs,4Common Terminology Criteria for Adverse Events (CTCAE) v5.0. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 2017https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50Google Scholar and (3) AEs leading to early termination. The secondary endpoint was efficacy measured by AK clearance. Exploratory analysis investigated an association between daylight irradiance and AK clearance. Twenty-four white men underwent treatment (17 face, 7 scalp). Mean age was 75 (range, 60-94) years. Mean baseline AK count was 10.8 ± 4.9, similar across groups. One participant in the conventional group discontinued treatment secondary to pain. One participant in the daylight group was lost to follow-up. Peak pain was lower during treatment in combination and daylight groups compared with conventional, with a difference of –3.4 (95% confidence interval [CI], –4.44 to –2.30; P < .0001) and –3.5 (95% CI, –4.57 to –2.42; P < .0001) (Fig 1). Pain remained lower in these groups compared with the conventional group, with a difference of –1.8 (95% CI, –2.95 to –0.80; P = .0007) and –1.8 (95% CI, –2.98 to –0.76; P = .0011). Composite LSR score peaked on day 8 for all groups and was significantly higher in the combination group compared with the conventional group, (2.13; 95% CI, 0.64-3.61; P = .005) (supplemental Fig 2; available at https://doi.org/10.17632/rccd7rb8yp.1). The most frequent application site AEs included pruritus (42%), burning/pain (38%), scaling (25%), and erythema (25%). Four grade 2 AEs were observed (supplemental Table I; available at https://doi.org/10.17632/rccd7rb8yp.1). There were no AE-related discontinuations. At day 84, mean AK reductions were 63.9% ± 24.9%, 66.4% ± 29.5%, and 61.8% ± 59.9% for the conventional, combination, and daylight groups, respectively. Daylight and combination PDT had lower overall and peak pain, but D8 LSR was higher for the combination group compared with conventional. This finding may be due to illumination with both blue light and daylight. The study, although not powered to detect statistically significant differences in treatment efficacies, found efficacy similar to historical controls.5Piacquadio D.J. Chen D.M. Farber H.F. et al.Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials.Arch Dermatol. 2004; 140: 41-46Crossref PubMed Scopus (211) Google Scholar AK clearance did not correlate with daylight solar irradiance (range, 8.5-1122.0 W/m2). To maximize the safety of daylight PDT, providers should emphasize avoidance of light exposure following treatment. Daylight and combination PDT have a safety profile similar to conventional PDT. The combination regimen of short incubation and blue light followed by daylight exposure is a practical and feasible option. Dr Crow is an investigator for clinical trials sponsored by Castle Biosciences , LEO Pharma , Sun Pharma , Pfizer , PellePharm , and Eli Lilly . Ms Aroyan is a research coordinator for clinical trials sponsored by Castle Biosciences , Menlo Therapeutics , LEO Pharma , Genentech , Sun Pharma , Regeneron , Pfizer , and Eli Lilly . Dr Arron is an investigator for clinical trials sponsored by LEO Pharma , Castle Biosciences , Menlo Therapeutics , Genentech , Sun Pharma , Pfizer , Regeneron , PellePharm , and Eli Lilly . She is a consultant to Enspectra Health, Rakuten Medical, and Gerson Lehrman Group. Drs Lazar, Tello, Saylor, and Griffith-Bauer have no relevant conflicts of interest to disclose.