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Efficacy of 3 different light doses in the treatment of actinic keratosis with 5-aminolevulinic acid photodynamic therapy: A randomized, observer-blinded, intrapatient, comparison study
THERAPY
Efficacy of 3 different light doses in the treatment of actinic keratosis with 5-aminolevulinic acid photodynamic therapy: A randomized, observer-blinded, intrapatient, comparison study Sonja Radakovic-Fijan, MD,a Ulrike Blecha-Thalhammer, MD,a Harald Kittler, MD,b Herbert Ho¨nigsmann, MD,a and Adrian Tanew, MDa Vienna, Austria Background: Topical 5-aminolevulinic acidebased photodynamic therapy (ALA-PDT) has been established in recent years as an effective treatment for disseminated actinic keratosis (AK). As yet, however, data are lacking to define the optimal light dose for activation of ALA-induced protoporphyrin IX in AK. Objective: In the present study our purpose was to compare the efficacy and tolerability of 3 different doses of red light for ALA-PDT of AK. Methods: Twenty-seven patients with at least 3 clearly definable, mild or moderate AKs on the scalp or face entered the study. After occlusion for 4 hours with 20% ALA, one AK each was irradiated at random with a single dose of 70, 100, or 140 J/cm2. PDT-induced pain was assessed by the patients by means of a visual analog scale that graded pain intensity between 0 and 10. Follow-up examinations were performed 1 and 3 months after PDT. Results: One month after PDT, the rate of complete remission (CR) was 89% for 70 J/cm2, 92% for 100 J/cm2, and 81% for 140 J/cm2. The CR rates at 3 months were 81% for 70 J/cm2, 77% for 100 J/cm2, and 69% for 140 J/cm2. No significant difference in therapeutic efficacy was found among the 3 light doses at either 1 month (P = .36) or 3 months (P = .96) after PDT. The degree of PDT-induced pain during irradiation was substantial and not statistically different (P = .06) for all 3 light doses. Limitations: The conclusions from this study are limited by the small sample size and only apply to topical ALA-PDT. Conclusion: Our results indicate that a red light dose of 70 J/cm2 may be sufficient for effective topical ALA-PDT of disseminated, mild to moderate AK on the face and scalp. ( J Am Acad Dermatol 2005;53:823-7.)
A
ctinic keratosis (AK) is the most common neoplastic skin lesion with a prevalence ranging from 11% to 25% in the Northern Hemisphere and from 40% to 50% in Australia.1 The
From the Division of Special and Environmental Dermatologya and the Division of General Dermatology,b Medical University of Vienna. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Adrian Tanew, MD, Division of Special and Environmental Dermatology, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.06.010
fact that 1% to 10% of AKs progress to squamous cell carcinoma and approximately 60% of all squamous cell carcinomas develop from AKs underscores the importance of early treatment.2,3 Cryotherapy and topical 5-fluorouracil are the most widely used treatment options for localized and multiple AKs, respectively. More recently, topical 5-aminolevulinic acidebased photodynamic therapy (ALA-PDT) has been shown in numerous studies to be an effective alternative treatment for AK, resulting in excellent cosmetic outcome.4,5 ALA is a precursor of the endogenous photosensitizer protoporphyrin IX that is preferentially synthesized and accumulated in neoplastic cells. Irradiation with visible light induces the formation of reactive oxygen species (in particular, singlet oxygen) that result in tumor destruction.6 For 823
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J AM ACAD DERMATOL NOVEMBER 2005
Table I. Complete response rates of AKs at 1 and 3 months after PDT with 70, 100, and 140 J/cm2 of red light Light dose (J/cm2)
70 (n = 26) 100 (n = 26) 140 (n = 26) All doses (N = 78)
Fig 1. Mean (1 standard deviation) clinical score of actinic keratoses before and 1 and 3 months after PDT treatment with 3 different light doses.
photoactivation of ALA-induced protoporphyrin IX, a range of doses in the red region of visible light is generally used; however, to date the optimal light dose for achieving the therapeutic effect in patients with neoplastic lesions has not been determined in clinical trials. In the present study we compared the efficacy and tolerability of topical ALA-PDT for AK by using 3 different light doses of 70, 100, and 140 J/cm2.
PATIENTS AND METHODS Twenty-seven patients (25 men, 2 women) with at least 3 AKs on the face or scalp were enrolled in the study. AKs were classified into 3 grades according to Olsen et al7: 1 = mild, 2 = moderate, 3 = severe. Only isolated AKs of grade 1 or 2 that were clearly definable were chosen for the study to warrant accurate relocation of the lesions at the follow-up visits. Grade 3 AKs were excluded from treatment because they are known from previous investigations to respond less favorably to PDT.8,9 Before ALA-PDT, all lesions were digitally photographed. Anatomical landmarks were marked for consistency of follow-up. Control photographs were taken at 1 and 3 months after PDT. The study was approved by our local Institutional Review Board and conducted according to Declaration of Helsinki priciples. All patients gave written consent to participate after having received detailed information on the purpose and design of the study. Treatment In each patient 3 AKs of comparable severity and location were chosen for a single PDT treatment with 3 different light doses. Forty-two AKs were localized on the scalp and 39 on the face. All lesions were evaluated by a blinded observer at baseline as well as at 1 and 3 months after PDT treatment. A clinical score was used that assessed erythema, hyperkera-
CR rate at 1 mo (%)
CR rate at 3 mo (%)
88.5 92.3 80.8 87.2
80.8 76.9 69.2 75.6
tosis, and thickness on a scale between 0 and 1.5 (0 = absent, 0.5 = slight, 1.0 = moderate, 1.5 = severe) with a maximal sum score of 4.5. Complete response (CR) was defined as a sum score of 0. The mean clinical score of all AKs at baseline was 2.1 (range, 1.0-3.5). All AKs were treated with 20% ALA hydrochloride (medac, Weidel, Germany) dissolved in an oil-inwater cream (Doritin, Asta Medica, Vienna, Austria). ALA was applied on the lesions and on 5 mm of surrounding normal skin and left under occlusion (Opraflex, Lohmann GmbH, Neuwied, Germany) for 4 hours. The dressing was then removed and remnants of the cream gently wiped off. Irradiation of the three selected AKs was done with a filtered high-pressure metal halide lamp (600-750 nm, Waldmann Medical Division PDT 1200, VillingenSchwenningen, Germany), at 100 mW/cm2 and a light dose of 70, 100, or 140 J/cm2, respectively. Pain during treatment was quantified by the patients on a 0 to 10 visual analog scale. In some patients who felt very intense pain, cooling with a cold water spray or a fan was performed. In addition to PDT-induced pain, any other adverse event, including the severity of the local phototoxic reaction, was recorded during and after treatment. Statistical analysis Data are given as mean and standard deviation unless otherwise specified. Analysis of variance for repeated measures was performed for comparison of the efficacy of the different light doses and for comparing PDT-induced pain scores at the different doses. All statistical analyses were performed by using the Statistical Package for the Social Sciences version 10.0 (SPSS Inc, Chicago, Ill) software package. All given P values are two-tailed and a P value less than .05 was considered to indicate statistical significance.
RESULTS One patient was excluded from evaluation because of unbearable pain during irradiation of the first AK, which necessitated discontinuation of
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Fig 2. A, Overview of the target lesions before treatment. B and C, AKs before and after ALAPDT treatment with a light dose of 140 J/cm2; D and E, before and after 70 J/cm2; F and G, before and after 100 J/cm2.
treatment. Three patients were not available for follow-up at 3 months after PDT. In these patients the last observation was carried forward for statistical analysis. In each of the 3 light dose groups, 26 AKs with a comparable mean baseline score were able to be evaluated for analysis (Fig 1). At 1 month after treatment the clearance rate of all lesions irrespective of the applied light dose was 87.2% (68/78 lesions). When stratified for the different light doses the CR rates were as follows: 88.5% (23/26) for 70 J/cm2, 92.3% (24/26) for 100 J/cm2, and 80.8% (21/26) for 140 J/cm2 (Table I). At 3 months after PDT, CR was found in 75.6% (59/78) of all lesions irrespective
of the applied light dose. The CR rates for the 3 light doses were 80.8% (21/26) for 70 J/cm2, 76.9% (20/26) for 100 J/cm2, and 69.2% (18/26) for 140 J/cm2. Reduction of the mean clinical baseline score at 1 month after PDT was 98.1% for the light dose of 70 J/cm2, 97.2% for 100 J/cm2, and 91.9% for 140 J/cm2. At the 3-month follow-up the score reduction was 90.0% for 70 J/cm2, 86.6% for 100 J/cm2, and 87.1% for 140 J/cm2 (Fig 1). Using analysis of variance for repeated measures, we analyzed whether the treatment effect depended on the light dose. There was a significant treatment effect for all groups. The mean clinical score of all PDT-treated
826 Radakovic-Fijan et al
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Fig 3. Mean pain score (1 standard deviation) during PDT treatment of AKs with 3 different light doses.
lesions declined from 2.1 6 0.7 at baseline to 0.1 6 0.3 at the first follow-up visit and to 0.3 6 0.6 at the second follow-up visit at 3 months after PDT (P \ .001). This treatment effect was similar in all 3 groups (Fig 2) and was independent of the applied light dose (P = .83 for the interaction between treatment effect and light dose). The mean score (6 standard deviation) of PDTassociated pain was 6.3 6 2.1 for 70 J/cm2, 6.8 6 1.9 for 100 J/cm2, and 6.9 6 1.8 for 140 J/cm2, respectively (Fig 3). The difference in mean pain score among the 3 light doses was not statistically significant (P = .06). We also did not find any correlation between pain intensity and the sequence in which the light doses were delivered to each patient or between pain intensity and response to PDT. Local phototoxic reactions apart from mild to moderate erythema included edema (15.3%), blistering (3.8%), and pustulation (7.7%) and were not dose dependent. All of these events were of short duration and completely reversible. The cosmetic outcome in all cured AKs was excellent, except in one patient; after additional sun exposure, postinflammatory hyperpigmentation developed in all 3 PDT-treated AKs.
DISCUSSION Treatment of AKs with ALA-PDT is a highly effective and safe method, resulting in excellent cosmetic outcome. For mild to moderate lesions on the face and scalp, CR rates between 71% and 100% have been reported after a single PDT treatment.4 To date no standard protocol for PDT for AKs has evolved, and variation exists with regard to ALA concentration, application time, light source, light intensity, and light dose. In previous studies using 10% to 20% ALA hydrochloride and incoherent red light sources, the average irradiation dose ranged between 100 and 160 J/cm2.8,10-12 However, to date
systematic data on the comparative therapeutic efficacy of different light doses are lacking. In the present controlled trial using 20% ALA hydrochloride in combination with a metal halide lamp, we could not find any difference between light doses ranging from 70 to 140 J/cm2 in terms of both response and recurrence rate. Since our study was performed as an intrapatient comparison approach, interindividual variations in the response to PDT that otherwise could have served as a confounding factor in interpreting the data can be excluded. These results clearly indicate that for ALA-PDT of mild to moderate AKs on the face or scalp, light doses higher than 70 J/cm2 do not result in increased therapeutic efficacy and actually represent overtreatment. We also did not find a significant correlation between the applied light dose and the intensity of PDT-induced pain or phototoxic skin reaction. Although we have seen a tendency toward higher light doses causing more pain, this finding was not statistically significant. In general local phototoxic skin reactions were well tolerated and resolved within a few days without further complications. Previous reports are in good agreement with the overall CR rates of 87.2% and 75.6% that were found in our study at 1 and 3 months after PDT, respectively. The drop in response rate between the 1- and 3-month follow-up examination can be interpreted as an apparent rather than real complete resolution of some AKs shortly after PDT. Residual malignant cells that are still in the epidermis but not apparent by visual inspection at the short-term follow-up will continue to proliferate and result in an early clinical recurrence of the AKs at a later examination. Data in the literature with regard to recurrence rates are controversial. Whereas some authors did not observe a drop in clearance rate between 1 and 3 months after PDT or after a mean follow-up period of 36 months, others reported recurrence rates of 28% between 6 and 12 months after PDT or 30% after a median follow-up period of 13 months, respectively.8,12-14 In a recent multicenter study comparing PDT using topical methylaminolevulinate with single cryotherapy for AKs of the face or scalp, two PDT sessions were given 1 week apart. At 3 months after PDT complete clearance was found in 91% of the lesions.15 As the authors themselves pointed out, short-term double-treatment might not be advisable since approximately 70% of AKs are already clear after a single PDT exposure. For that reason we only performed one PDT session followed by clinical examinations at 1 and 3 months after PDT. Repeat treatment was restricted to those lesions that showed an incomplete response at the second follow-up visit.
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To our knowledge, this is the first systematic study comparing the efficacy and tolerability of 3 different light doses for ALA-PDT of AKs. Our results indicate that an irradiation dose of 70 J/cm2 (and possibly even less) is as effective as up to twice that dose in the treatment of mild to moderate AKs on the scalp and face. We therefore recommend starting with one PDT session at an irradiation dose of 70 J/cm2 followed by a clinical examination 3 months later. Lesions showing an incomplete response at that time might then receive a second PDT treatment using the same light dose. REFERENCES 1. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131:455-64. 2. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol 2002;146(Suppl):20-3. 3. Jeffes EWB, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol 2000;1:167-79. 4. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552-67. 5. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, CalzavaraPinton PG, Zane C, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol 2002;47:258-62. 6. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992;55:145-57. 7. Olsen EA, Abernethy ML, Kulp-Shorten C, Callen JP, Glazer SD, Huntley A, et al. A double-blinded, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic
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keratoses on the head and neck. J Am Acad Dermatol 1991;24:738-43. Szeimies RM, Karrer S, Sauerwald A, Landthaler M. Photodynamic therapy with topical application of 5-aminolevulinic acid in the treatment of actinic keratoses: an initial clinical study. Dermatology 1996;192:246-51. Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor RJ. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001;45:96-104. Fijan S, Ho¨nigsmann H, Ortel B. Photodynamic therapy of epithelial skin tumours using delta-aminolaevulinic acid and desferrioxamine. Br J Dermatol 1995;133:282-8. Karrer S, Ba¨umler W, Abels C, Hohenleutner U, Landthaler M, Szeimies RM. Long-pulse dye laser for photodynamic therapy: investigations in vitro and in vivo. Lasers Surg Med 1999;25: 51-9. Varma S, Wilson H, Kurwa HA, Gambles B, Charman C, Pearse AD, et al. Bowen‘s disease, solar keratoses and superficial basal cell carcinomas treated by photodynamic therapy using a large-field incoherent light source. Br J Dermatol 2001; 144:567-74. Stefanidou M, Tosca A, Themelis G, Vazgiouraki E, Balas C. In vivo fluorescence kinetics and photodynamic therapy efficacy of d-aminolevulinic acid-induced porphyrins in basal cell carcinomas and actinic keratoses; implications for optimization of photodynamic therapy. Eur J Dermatol 2000;5:351-6. Fink-Puches R, Hofer A, Smolle J, Kerl H. Primary clinical response and long-term follow up of solar keratoses treated with topically applied 5-aminolevulinic acid and irradiation by different wave bands of light. J Photochem Photobiol B: Biol 1997;41:145-51. Freeman M, Vinciullo C, Francis D, Spelman L, Nguyen R, Fergin P, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatol Treat 2003;14:99-106.
Efficacy of 3 different light doses in the treatment of actinic keratosis with 5-aminolevulinic acid photodynamic therapy: A randomized, observer-blinded, intrapatient, comparison study Sonja Radakovic-Fijan, MD,a Ulrike Blecha-Thalhammer, MD,a Harald Kittler, MD,b Herbert Ho¨nigsmann, MD,a and Adrian Tanew, MDa Vienna, Austria Background: Topical 5-aminolevulinic acidebased photodynamic therapy (ALA-PDT) has been established in recent years as an effective treatment for disseminated actinic keratosis (AK). As yet, however, data are lacking to define the optimal light dose for activation of ALA-induced protoporphyrin IX in AK. Objective: In the present study our purpose was to compare the efficacy and tolerability of 3 different doses of red light for ALA-PDT of AK. Methods: Twenty-seven patients with at least 3 clearly definable, mild or moderate AKs on the scalp or face entered the study. After occlusion for 4 hours with 20% ALA, one AK each was irradiated at random with a single dose of 70, 100, or 140 J/cm2. PDT-induced pain was assessed by the patients by means of a visual analog scale that graded pain intensity between 0 and 10. Follow-up examinations were performed 1 and 3 months after PDT. Results: One month after PDT, the rate of complete remission (CR) was 89% for 70 J/cm2, 92% for 100 J/cm2, and 81% for 140 J/cm2. The CR rates at 3 months were 81% for 70 J/cm2, 77% for 100 J/cm2, and 69% for 140 J/cm2. No significant difference in therapeutic efficacy was found among the 3 light doses at either 1 month (P = .36) or 3 months (P = .96) after PDT. The degree of PDT-induced pain during irradiation was substantial and not statistically different (P = .06) for all 3 light doses. Limitations: The conclusions from this study are limited by the small sample size and only apply to topical ALA-PDT. Conclusion: Our results indicate that a red light dose of 70 J/cm2 may be sufficient for effective topical ALA-PDT of disseminated, mild to moderate AK on the face and scalp. ( J Am Acad Dermatol 2005;53:823-7.)
A
ctinic keratosis (AK) is the most common neoplastic skin lesion with a prevalence ranging from 11% to 25% in the Northern Hemisphere and from 40% to 50% in Australia.1 The
From the Division of Special and Environmental Dermatologya and the Division of General Dermatology,b Medical University of Vienna. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Adrian Tanew, MD, Division of Special and Environmental Dermatology, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.06.010
fact that 1% to 10% of AKs progress to squamous cell carcinoma and approximately 60% of all squamous cell carcinomas develop from AKs underscores the importance of early treatment.2,3 Cryotherapy and topical 5-fluorouracil are the most widely used treatment options for localized and multiple AKs, respectively. More recently, topical 5-aminolevulinic acidebased photodynamic therapy (ALA-PDT) has been shown in numerous studies to be an effective alternative treatment for AK, resulting in excellent cosmetic outcome.4,5 ALA is a precursor of the endogenous photosensitizer protoporphyrin IX that is preferentially synthesized and accumulated in neoplastic cells. Irradiation with visible light induces the formation of reactive oxygen species (in particular, singlet oxygen) that result in tumor destruction.6 For 823
824 Radakovic-Fijan et al
J AM ACAD DERMATOL NOVEMBER 2005
Table I. Complete response rates of AKs at 1 and 3 months after PDT with 70, 100, and 140 J/cm2 of red light Light dose (J/cm2)
70 (n = 26) 100 (n = 26) 140 (n = 26) All doses (N = 78)
Fig 1. Mean (1 standard deviation) clinical score of actinic keratoses before and 1 and 3 months after PDT treatment with 3 different light doses.
photoactivation of ALA-induced protoporphyrin IX, a range of doses in the red region of visible light is generally used; however, to date the optimal light dose for achieving the therapeutic effect in patients with neoplastic lesions has not been determined in clinical trials. In the present study we compared the efficacy and tolerability of topical ALA-PDT for AK by using 3 different light doses of 70, 100, and 140 J/cm2.
PATIENTS AND METHODS Twenty-seven patients (25 men, 2 women) with at least 3 AKs on the face or scalp were enrolled in the study. AKs were classified into 3 grades according to Olsen et al7: 1 = mild, 2 = moderate, 3 = severe. Only isolated AKs of grade 1 or 2 that were clearly definable were chosen for the study to warrant accurate relocation of the lesions at the follow-up visits. Grade 3 AKs were excluded from treatment because they are known from previous investigations to respond less favorably to PDT.8,9 Before ALA-PDT, all lesions were digitally photographed. Anatomical landmarks were marked for consistency of follow-up. Control photographs were taken at 1 and 3 months after PDT. The study was approved by our local Institutional Review Board and conducted according to Declaration of Helsinki priciples. All patients gave written consent to participate after having received detailed information on the purpose and design of the study. Treatment In each patient 3 AKs of comparable severity and location were chosen for a single PDT treatment with 3 different light doses. Forty-two AKs were localized on the scalp and 39 on the face. All lesions were evaluated by a blinded observer at baseline as well as at 1 and 3 months after PDT treatment. A clinical score was used that assessed erythema, hyperkera-
CR rate at 1 mo (%)
CR rate at 3 mo (%)
88.5 92.3 80.8 87.2
80.8 76.9 69.2 75.6
tosis, and thickness on a scale between 0 and 1.5 (0 = absent, 0.5 = slight, 1.0 = moderate, 1.5 = severe) with a maximal sum score of 4.5. Complete response (CR) was defined as a sum score of 0. The mean clinical score of all AKs at baseline was 2.1 (range, 1.0-3.5). All AKs were treated with 20% ALA hydrochloride (medac, Weidel, Germany) dissolved in an oil-inwater cream (Doritin, Asta Medica, Vienna, Austria). ALA was applied on the lesions and on 5 mm of surrounding normal skin and left under occlusion (Opraflex, Lohmann GmbH, Neuwied, Germany) for 4 hours. The dressing was then removed and remnants of the cream gently wiped off. Irradiation of the three selected AKs was done with a filtered high-pressure metal halide lamp (600-750 nm, Waldmann Medical Division PDT 1200, VillingenSchwenningen, Germany), at 100 mW/cm2 and a light dose of 70, 100, or 140 J/cm2, respectively. Pain during treatment was quantified by the patients on a 0 to 10 visual analog scale. In some patients who felt very intense pain, cooling with a cold water spray or a fan was performed. In addition to PDT-induced pain, any other adverse event, including the severity of the local phototoxic reaction, was recorded during and after treatment. Statistical analysis Data are given as mean and standard deviation unless otherwise specified. Analysis of variance for repeated measures was performed for comparison of the efficacy of the different light doses and for comparing PDT-induced pain scores at the different doses. All statistical analyses were performed by using the Statistical Package for the Social Sciences version 10.0 (SPSS Inc, Chicago, Ill) software package. All given P values are two-tailed and a P value less than .05 was considered to indicate statistical significance.
RESULTS One patient was excluded from evaluation because of unbearable pain during irradiation of the first AK, which necessitated discontinuation of
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Fig 2. A, Overview of the target lesions before treatment. B and C, AKs before and after ALAPDT treatment with a light dose of 140 J/cm2; D and E, before and after 70 J/cm2; F and G, before and after 100 J/cm2.
treatment. Three patients were not available for follow-up at 3 months after PDT. In these patients the last observation was carried forward for statistical analysis. In each of the 3 light dose groups, 26 AKs with a comparable mean baseline score were able to be evaluated for analysis (Fig 1). At 1 month after treatment the clearance rate of all lesions irrespective of the applied light dose was 87.2% (68/78 lesions). When stratified for the different light doses the CR rates were as follows: 88.5% (23/26) for 70 J/cm2, 92.3% (24/26) for 100 J/cm2, and 80.8% (21/26) for 140 J/cm2 (Table I). At 3 months after PDT, CR was found in 75.6% (59/78) of all lesions irrespective
of the applied light dose. The CR rates for the 3 light doses were 80.8% (21/26) for 70 J/cm2, 76.9% (20/26) for 100 J/cm2, and 69.2% (18/26) for 140 J/cm2. Reduction of the mean clinical baseline score at 1 month after PDT was 98.1% for the light dose of 70 J/cm2, 97.2% for 100 J/cm2, and 91.9% for 140 J/cm2. At the 3-month follow-up the score reduction was 90.0% for 70 J/cm2, 86.6% for 100 J/cm2, and 87.1% for 140 J/cm2 (Fig 1). Using analysis of variance for repeated measures, we analyzed whether the treatment effect depended on the light dose. There was a significant treatment effect for all groups. The mean clinical score of all PDT-treated
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Fig 3. Mean pain score (1 standard deviation) during PDT treatment of AKs with 3 different light doses.
lesions declined from 2.1 6 0.7 at baseline to 0.1 6 0.3 at the first follow-up visit and to 0.3 6 0.6 at the second follow-up visit at 3 months after PDT (P \ .001). This treatment effect was similar in all 3 groups (Fig 2) and was independent of the applied light dose (P = .83 for the interaction between treatment effect and light dose). The mean score (6 standard deviation) of PDTassociated pain was 6.3 6 2.1 for 70 J/cm2, 6.8 6 1.9 for 100 J/cm2, and 6.9 6 1.8 for 140 J/cm2, respectively (Fig 3). The difference in mean pain score among the 3 light doses was not statistically significant (P = .06). We also did not find any correlation between pain intensity and the sequence in which the light doses were delivered to each patient or between pain intensity and response to PDT. Local phototoxic reactions apart from mild to moderate erythema included edema (15.3%), blistering (3.8%), and pustulation (7.7%) and were not dose dependent. All of these events were of short duration and completely reversible. The cosmetic outcome in all cured AKs was excellent, except in one patient; after additional sun exposure, postinflammatory hyperpigmentation developed in all 3 PDT-treated AKs.
DISCUSSION Treatment of AKs with ALA-PDT is a highly effective and safe method, resulting in excellent cosmetic outcome. For mild to moderate lesions on the face and scalp, CR rates between 71% and 100% have been reported after a single PDT treatment.4 To date no standard protocol for PDT for AKs has evolved, and variation exists with regard to ALA concentration, application time, light source, light intensity, and light dose. In previous studies using 10% to 20% ALA hydrochloride and incoherent red light sources, the average irradiation dose ranged between 100 and 160 J/cm2.8,10-12 However, to date
systematic data on the comparative therapeutic efficacy of different light doses are lacking. In the present controlled trial using 20% ALA hydrochloride in combination with a metal halide lamp, we could not find any difference between light doses ranging from 70 to 140 J/cm2 in terms of both response and recurrence rate. Since our study was performed as an intrapatient comparison approach, interindividual variations in the response to PDT that otherwise could have served as a confounding factor in interpreting the data can be excluded. These results clearly indicate that for ALA-PDT of mild to moderate AKs on the face or scalp, light doses higher than 70 J/cm2 do not result in increased therapeutic efficacy and actually represent overtreatment. We also did not find a significant correlation between the applied light dose and the intensity of PDT-induced pain or phototoxic skin reaction. Although we have seen a tendency toward higher light doses causing more pain, this finding was not statistically significant. In general local phototoxic skin reactions were well tolerated and resolved within a few days without further complications. Previous reports are in good agreement with the overall CR rates of 87.2% and 75.6% that were found in our study at 1 and 3 months after PDT, respectively. The drop in response rate between the 1- and 3-month follow-up examination can be interpreted as an apparent rather than real complete resolution of some AKs shortly after PDT. Residual malignant cells that are still in the epidermis but not apparent by visual inspection at the short-term follow-up will continue to proliferate and result in an early clinical recurrence of the AKs at a later examination. Data in the literature with regard to recurrence rates are controversial. Whereas some authors did not observe a drop in clearance rate between 1 and 3 months after PDT or after a mean follow-up period of 36 months, others reported recurrence rates of 28% between 6 and 12 months after PDT or 30% after a median follow-up period of 13 months, respectively.8,12-14 In a recent multicenter study comparing PDT using topical methylaminolevulinate with single cryotherapy for AKs of the face or scalp, two PDT sessions were given 1 week apart. At 3 months after PDT complete clearance was found in 91% of the lesions.15 As the authors themselves pointed out, short-term double-treatment might not be advisable since approximately 70% of AKs are already clear after a single PDT exposure. For that reason we only performed one PDT session followed by clinical examinations at 1 and 3 months after PDT. Repeat treatment was restricted to those lesions that showed an incomplete response at the second follow-up visit.
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To our knowledge, this is the first systematic study comparing the efficacy and tolerability of 3 different light doses for ALA-PDT of AKs. Our results indicate that an irradiation dose of 70 J/cm2 (and possibly even less) is as effective as up to twice that dose in the treatment of mild to moderate AKs on the scalp and face. We therefore recommend starting with one PDT session at an irradiation dose of 70 J/cm2 followed by a clinical examination 3 months later. Lesions showing an incomplete response at that time might then receive a second PDT treatment using the same light dose. REFERENCES 1. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131:455-64. 2. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol 2002;146(Suppl):20-3. 3. Jeffes EWB, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol 2000;1:167-79. 4. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552-67. 5. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, CalzavaraPinton PG, Zane C, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol 2002;47:258-62. 6. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992;55:145-57. 7. Olsen EA, Abernethy ML, Kulp-Shorten C, Callen JP, Glazer SD, Huntley A, et al. A double-blinded, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic
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