Photodynamic therapy simplified: nonprepared, moderate‐grade actinic keratosis lesions respond equally well to 5‐aminolaevulinic acid patch photodynamic therapy as do mild lesions

DEAR EDITOR, Photodynamic therapy (PDT) using 5-aminolaevulinic acid (5-ALA) or its methyl ester (MAL) has long been used for the treatment of actinic keratosis (AK). The pharmaceutical active ingredient is incorporated either into a liquid or semisolid (solution: Levulan , cream: Metvix , gel: Ameluz ) or into a solid formulation (patch: Alacare ). The 5-ALA patch offers a number of advantages over currently available formulations: the light-blocking patch allows very simple and accurate local dosing and one-step residue-free product removal after incubation. Results from clinical trials with liquid and semisolid 5-ALA and MAL formulations, as well as clinical experience, suggest that the grade of the AK lesion may influence efficacy. However, the current body of evidence is not uniform. The various clinical trials show some differences in treatment modalities and in the definitions for grading AKs. For the liquid 5-ALA formulation, clinical studies have indicated that clearance rates (defined as the percentage of treated AK lesions showing complete clinical clearance after PDT) were better for mild-grade than for moderate-grade lesions. The percentage of patients completely cleared 12 months after PDT with a semisolid 5-ALA gel formulation was 14% higher for mildthan for moderate-grade lesions. Also, for the semisolid MAL formulation, clinical studies indicate that clearance rates are slightly better for mild-grade than for moderate-grade lesions. The 5-ALA patch formulation was applied to mildand moderate-grade AK lesions in clinical trials without pretreatment of the lesions. AK lesion grades were defined according to Cockerell, which do include hyperkeratosis for moderate lesions, as opposed to the definition of Olsen et al. The phase II dose-finding study showed a very comparable efficacy result for both mild and moderate AK lesions in the 4-h patch-application group. Phase III data of two patient randomized clinical studies, AK03 and AK04, were analysed post hoc with focus on lesion-grade-specific results. Complete clinical clearance was analysed on a lesion basis in both studies, taking the statistical correlation between lesion responses within patients into account. Further analyses consisted of the computation of odds ratios, including 95% confidence intervals, for the factor ‘lesion grade’ to describe the strength of association between lesion grade and clearance result in relation to the comparators, placebo patch PDT and cryotherapy. With respect to the efficacy of 5-ALA patch PDT, clearance rates of mild and moderate AK lesions were comparable at both 12 weeks (AK03: 83% mild AK, 82% moderate AK; AK04: 90% mild AK, 87% moderate AK) and 12 months (AK03: 68% mild AK, 59% moderate AK; AK04: 80% mild AK, 78% moderate AK) after a single treatment. Odds ratios and confidence intervals were calculated in the primary efficacy analysis populations for comparison with cryosurgery (AK04) and placebo PDT (AK03, AK04) (Table 1). The results statistically confirm the superiority of 5-ALA patch PDT over placebo patch PDT (both confirmatory trials) and cryosurgery (clinical trial AK04) for both lesion grades. A statistical comparison between the results per lesion grade was not performed. Recurrence rates were calculated on the basis of the data obtained 12 months after 5-ALA patch PDT. Again, no statistically significant differences were found in the analyses. In AK04, the estimates for the recurrence rates 12 months after therapy were 12% for mild-grade and 10% for moderate-grade AK treated with 5-ALA patch PDT. The respective AK03 data were 18% for mild lesions and 28% for moderate lesions after 5-ALA patch PDT. PDT is known to provide excellent cosmetic results. Therefore, pigmentation of the treated AK lesions was followed up over the whole study period. In study AK03 hypopigmentation at week 12 was observed only in a small number of moderatebut not in mild-grade lesions. In study AK04 no difference between mildand moderate-grade lesions was observed. Hypoor hyperpigmentation 12 months after 5-ALA patch PDT played a negligible role, with no noticeable difference between lesion grades. Furthermore, the cosmetic outcome as assessed by investigator and patient did not differ between mildand moderate-grade lesions (Table 2). Regarding tolerability, there was no detectable difference between mildand moderate-grade AK lesions for local reactions after 5-ALA patch PDT (Table 2). The results of this in-depth analysis of the two previously reported confirmative phase III trials investigating 5-ALA patch PDT thus show no detectable difference in efficacy or tolerability between the treated lesion grades, mild and moderate. The absence of an effect of lesion grade on clearance rates after 5-ALA patch PDT contrasts with what has been reported for 5-ALA gel and MAL cream, where significant differences between recurrence rates were noted in favour of mild AK. For MAL cream PDT it was reported that even the localization