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Regarding recently published article on Safety and Efficacy of Aminolevulinic Acid 10% Topical Gel versus Aminolevulinic Acid 20% Topical Solution Followed by Blue-light Photodynamic Therapy for Treatment of Actinic Keratosis

Dear Editor:

In their article, “Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: A randomized, double-blind study,” Nestor et al assessed the response of actinic keratosis (AK) lesions in two 25-cm2 areas of skin in 40 subjects. Topical 5-aminolevulinic acid (ALA) 10% gel (GEL) was applied to one area, and ALA 20% solution (SOL) was applied to the other. After a one-hour incubation period, both areas were exposed to blue light (BLU-U) without prior curettage or occlusion. The authors acknowledged that their study conditions were a departure from labeling indications. Prescribing information for SOL indicates a 14- to 18-hour incubation period after lesional application prior to blue-light exposure, although shorter incubations after broad application have been shown to be effective and well tolerated.2 For GEL, the prescribing information calls for curettage and “roughening” of lesions, as well as occlusion of treated areas for three hours prior to red-light exposure.3 Nestor et al reported that, in an attempt to mimic treatment conditions more typically used in clinical practice, they did not include those steps in their protocol. The authors concluded that, under typical clinical conditions using blue light, the efficacies of GEL and SOL were equivalent and there were significantly more local skin reactions with SOL.

To ensure appropriate integration of these results into decision-making related to patient care, more study details are needed. In particular, rigorous statistical analyses were lacking. Equivalent is a statistical term that implies a rigorous comparison between groups, but here the p<0.001 value cited as a significant test result referred only to each treated area (Day 84) in comparison with its corresponding baseline (Day 0) rather than to comparisons between treatment groups. Also, a primary investigator associated with the study stated in the summary that it is impossible to determine statistically significant differences between reduction rates in each arm (95% for GEL vs. 94% for SOL) with a sample size of only 40 patients.3 To actually compare the two treatment groups, the mean change (±standard error) would be required, and, if equivalence tests had low power due to the limited sample size, a significance test, such as analysis of variance, could be used to compare the treatments adjusted by baseline. However, tables and tests with summary statistics (i.e., mean, median, standard deviation) for baseline values and changes from baseline were not provided. 

Other information would have been helpful to allow for a more meaningful evaluation. For example, how much of each product was applied? Prescribing information for GEL indicates application of a 1mm-thick layer not to exceed 2g (one tube); for SOL, two applications are indicated, with adequate drying time allowed for in between applications and without specific limitations on treatment area or volume. Under real-world conditions, not all patients return for a second treatment; therefore, knowing the percent of areas of each group that achieved 100-percent clearance after one treatment (Day 28) might be helpful. It was unclear whether the endpoint of “100-percent clearance” refers only to those lesions treated at baseline (mapped and tracked) or whether it refers to any new lesions in the treated field, regardless of prior history. Finally, it would have been interesting to learn about recurrence rates and rates of new lesion occurrence in the context of both formulations.

Furthermore, the majority of local skin reaction (LSR) scores in Figure 4 were based on patient self-reporting (diary entries), which raises the question of how carefully patients were trained in the identification and grading of LSRs. “Irritation” was not evaluated, although that parameter was documented as affecting 72 percent of subjects on the ALA product labeling3 when administered with the approved red-light device.

Finally, evolving concepts regarding mechanisms of PDT action demand that any conclusion about efficacy should be made with caution. AK clearance appears to be mediated by local immune or inflammatory processes, which might not be linearly related to photosensitizer dose. In other words, clearance data after a single PDT treatment might be governed by a threshold effect independent of the administered dose of the active agent. In support of this idea, Nestor et al reported clearance rates of 58 percent and 52 percent after single treatments of SOL and GEL, respectively. A previous report on single administration of a blue-light PDT after short incubation showed the following clearance values: 53 percent after two hours, broad application; 57 percent after two hours, spot application; and 57 percent after three hours, broad application.2 These values are remarkably similar to those in the study by Nestor et al. Current uncertainties about mechanism even raise the possibility that assessments of small treatment areas might limit our ability to generalize GEL versus SOL outcomes to large skin treatment areas more typical of real-world practice.

With regard,

Edward V. Maytin, MD, PhD; Jeanett Segal, MD; and Anna Houlihan, MA

Dr. Maytin is with the Department of Dermatology and the Department of Biomedical Engineering at the Lerner Research Institute Cleveland Clinic in Cleveland, Ohio and the Wellman Center for Photomedicine at Massachusetts General Hospital, Harvard Medical School in Boston, Massachusetts.Dr. Segal and Ms. Houlihan are with Medical Affairs at Sun Pharmaceutical Industries, Inc. in Princeton, New Jersey, and Wilmington, Massachusetts, respectively.

Disclosures. Dr. Maytin serves on the scientific advisory board of Sun Pharmaceutical Industries Ltd. Dr. Segal and Ms. Houlihan are employees of Sun Pharmaceutical Industries Ltd. with medial affairs responsibilities related to Levulan®-BluU photodynamic therapy.

References

  1. Nestor MS, Berman B, Patel J, Lawson A. Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: a randomized, double-blind study. J Clin Aesthet Dermatol. 2019;12(3):32–38.
  2. Pariser DM, Houlihan A, Ferdon MB, et al. Randomized vehicle-controlled study of short drug incubation aminolevulinic acid photodynamic therapy for actinic keratoses of the face or scalp. Dermatol Surg. 2016;42(3):296–304. 
  3. Daily Med site. Ameluz—aminolevulinic acid hydrochloride gel drug label information. 25 Jun 2019. National Institutes of Health. US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=650daa9f-aeec-49ce-95b9-5fa20b988afd. 
  4. Berman B, Bhatia N, Cohen J, et al. A practical approach: field treatment of AKs with PDT [Insert]. Pract Dermatol. 2018;(9):2–6. 

Author Response

We appreciate the observations and comments from Maytin et al. The protocol of the study was designed to mimic real world use of both topical 5 ALA 10% gel and 20% solution. Regarding the application process, the gel was applied sufficiently to cover the 25cm² studied areas, with no specific intention or requirement of having at least 1mm-thick coverage, and the solution was applied in two applications with adequate drying time between applications. In both cases, incubation (without curettage or occlusion) for one hour was followed by 1000 seconds of blue light illumination (10J/cm2). 

As we indicated in our article,1 statistical comparison of efficacies in reduction rates of actinic keratoses by each treatment (95% for ALA-gel vs. 94% for ALA-solution) with a sample size of only 40 patients studied might benefit from a greater number of participants (our study included 40 participants, in which reduction rates of 95% vs. 94% were observed in ALA-gel vs. ALA solution groups).4 Indeed, these reductions in the number of actinic keratoses compared to baseline are highly statistically significant for each treatment, and it has recently been shown that evaluating the percent reduction in the number of actinic keratosis from baseline is independent from the number of actinic keratoses at baseline and is therefore the most appropriate assessment accepted by the United States Food and Drug Administration (FDA) regarding whether a treatment is indeed a “field therapy.”2 We appreciate the comment by Maytin et al that “rigorous statistical analyses” would be required to statistically compare the effectiveness of the two treatments we studied; however, although the observed efficacy rates of 95 and 94 percent might theoretically be subjected to further statistical analyses to determine whether the one-percent difference is statistically significant, such analyses of statistical equivalence would yield no useful clinical information.

The authors of the letter point out correctly that, in all likelihood, not all patients return for a second PDT treatment in the real world; however, the majority of patients do so in the real world and in all clinical studies of the gel and solution; therefore, the primary efficacy of this study was after two treatments. Additionally, our study clearly shows that two treatment courses of either topical 5 ALA 10% gel or 20% solution appear to be more efficacious in clearing actinic keratoses than one treatment course. Using FDA guidelines, the endpoint of “100-percent clearance” in the treated field means clearance of all actinic keratosis in the treated field, whether they were present at baseline or developed during the course of the study and then cleared. Although Maytin et al indicate that it would be interesting to quantify recurrence rates and rates of new lesion occurrence, such evaluations were not the focus of the study. As suggested in the letter, rather than evaluating “irritation,” we quantified validated local skin reaction (LSR) scores and pain, itch and erythema, which are the specific components present in “irritation”.

Maytin et al note that we have reported clearance rates of 58 and 52 percent after a single treatment of solution and gel, respectively, and that previous reports on single administration of solution PDT indicated “remarkably similar “results. We cannot disagree that “current uncertainty about mechanism” might possibly limit generalization of outcomes to larger skin treatment areas.

With regard,

Mark Nestor, MD, PhD; Brian Berman, MD, PhD; Jigesh Patel, BS; and Alec Lawson

Drs. Nestor and Berman and Messrs. Patel and Lawson are with the Center for Clinical and Cosmetic Research in Aventura, Florida. Drs. Nestor and Berman are also with the Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine in Miami, Florida. 

References

  1. Nestor MS, Berman B, Patel J, Lawson A. Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: a randomized, double-blind study. J Clin Aesthet Dermatol. 2019;12(3):32–38.
  2. Skov T, Stockfleth E, Szeimies RM, Berman B. Efficacy  endpoints in clinical trials in actinic keratoses. Dermatol Ther (Heidelb). 2018;8(3):425–433.
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