Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light

THERAPY

Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light Edward W. Jeffes, MD, PhD,a,b Jerry L. McCullough, PhD,a Gerald D. Weinstein, MD,a Ross Kaplan, MD,a Scott D. Glazer, MD,d and J. Richard Taylor, MDc Irvine and Long Beach, California, Miami, Florida, and Buffalo Grove, Illinois Background: Aminolevulinic acid hydrochloride (ALA, Levulan) applied topically to actinic keratoses (AKs) leads to accumulation of the photosensitizer protoporphyrin IX, which, when activated by exposure to light, eradicates AKs. Objective: We examined the safety and efficacy of photodynamic therapy using topical 20% ALA in a solution formulation and varying blue light doses to treat multiple AKs on the face and scalp. Method: This is a multicenter, investigator-blinded, randomized, vehicle-controlled study. Results: Thirty-six patients with clinically typical AKs were treated with 20% ALA; 14 to 18 hours later, they were irradiated with a nonlaser fluorescent blue light source. With the optimal light dose of 10 J/cm2, 88% of the AKs completely cleared 8 weeks after a single photodynamic treatment, compared with 6% after treatment with vehicle and light. Conclusion: Topical ALA PDT using a nonlaser, blue light source is an effective treatment for multiple AKs. (J Am Acad Dermatol 2001;45:96-104.)

T

he topical application of aminolevulinic acid HCl (ALA; Levulan by DUSA Pharmaceuticals Inc, Valhalla, NY) on skin leads to the accumulation of the endogenous photosensitizer protoporphyrin IX (PpIX) in epidermal cells. Conversion of ALA to PpIX occurs in skin cells by enzymes in the heme biosynthetic pathway. Rapidly proliferating skin cells, such as those in actinic keratoses (AKs) and psoriasis, convert more ALA to PpIX than do less rapidly proliferating normal epidermal cells.1 The tissue-specific phototoxicity resulting from the topical administration of exogenous ALA provides a basis for using ALA-induced PpIX for photodynamic therapy (PDT).1 PDT using topical ALA has been shown to be

From the Department of Dermatology, University of California, Irvinea; the Veterans Affairs Medical Center, Long Beachb; the Veterans Affairs Medical Center, Miamic; and Buffalo Grove.d Supported in part by a grant from DUSA Pharmaceuticals, Inc, Valhalla, NY. Dr Jeffes has been a consultant for DUSA Pharmaceuticals but has no financial interest in the company. Accepted for publication Nov 7, 2000. Reprint requests: Edward W. Jeffes, MD, PhD, Department of Dermatology, C340 Medical Sciences, University of California, Irvine, Irvine, CA 92697. 16/1/114288 doi:10.1067/mjd.2001.114288

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efficacious in the treatment of a variety of superficial epithelial cutaneous malignancies, including basal cell carcinoma and squamous cell carcinoma in situ (Bowen’s disease),2-5 and AK.1-3 We have recently shown that topical 20% ALA cream photoactivated with red (630 nm) laser light is an effective therapy of AKs.6 Red laser light was chosen in this original study to maximize both the depth of penetration and photoactivation of the PpIX. The amount of red light required to reach the maximum response with ALA PDT of AKs was 10 J/cm2 (the lowest fluence studied in this investigation). The current study evaluated a more practical therapy of AKs using a nonlaser, fluorescent blue light source, and a new solution formulation of ALA. Because PpIX is more efficiently photoactivated by blue light (Soret band) than red light, and because pathologic changes in AKs are superficially placed in the epidermis, blue light may be effective in photoactivating PpIX in AKs. Unlike the cream used in the previous study, the new ALA solution formulation does not require occlusion for effective percutaneous penetration and subsequent conversion to PpIX after application. The present investigator-blinded, randomized, vehicle-controlled study extends the observations in the last study and evaluates the effectiveness

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of treating multiple AKs of the face and scalp with topical 20% ALA solution and a nonlaser, fluorescent blue light source at fluences ranging from 2 to 10 J/cm2.

PATIENTS AND METHODS Patient population Thirty-six patients (6 females, 30 males; median age, 68.8 years; range, 38-100 years) each with at least 4 AKs on the face or scalp were enrolled in the study. On each patient 2 AKs were treated with vehicle and 2 with 20% ALA (see below for complete description). The 3 study sites were the Department of Dermatology, University of California, Irvine; Veterans Affairs Medical Center, Miami; and a private dermatology office, Buffalo Grove, Ill. Clinically typical AKs were selected by the investigator as scaly erythematous papules and plaques devoid of cystic pores or a papillomatous surface (to exclude seborrheic keratosis and verrucae). Lesions were clinically graded by means of criteria similar to those reported by Olsen et al.7 The criteria for each grade of AK were as follows: grade 1: mild, lesions slightly palpable, with AKs more readily felt than seen; grade 2: moderate, moderately thick AKs, easily seen and felt; or grade 3: severe, very thick or hyperkeratotic AKs. Only grade 1 or grade 2 AKs were included in the study. Hyperkeratotic, hypertrophic grade 3 AKs were excluded because of previous experience suggesting these did not respond well to PDT, and that most typical AKs on the face and scalp are grades 1 and 2.6 The mean area of the AKs determined by the product of the longest dimensions of the target lesion was 0.46 cm2 for ALAtreated lesions and 0.51 cm2 for vehicle-treated lesions; these are not statistically different. Further analysis of baseline data demonstrates that the distribution of AK thickness was not statistically significantly different when ALA, vehicle, or light dose groups were compared. Patients were excluded who had received previous treatment of target AKs, who had concurrent use of photosensitizing drug(s), or who had used nonsteroidal anti-inflammatory drugs 1 week before entry into the study; topical steroids, retinoids (Retin A), or topical alpha-hydroxyacids in the preceding 2 weeks; systemic steroids in the preceding 4 weeks; topical application of 5fluorouracil cream, masoprocol (Actinex), systemic chemotherapeutic agents, immunotherapy, or retinoids in the preceding 2 months. Pregnant or nursing women or patients with a history of cutaneous photosensitivity were also excluded. The study was approved by the local human patient research committee at each site. Each patient received comprehensive information regarding the

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nature of the study and written informed consent was obtained before treatment. Study design This was a multicenter, investigator-blinded, randomized, vehicle-controlled, light dose-ranging study in patients with multiple, discrete grade 1 or 2 AKs of the face and scalp. Each patient had a minimum of 4 target lesions with 2 lesions being randomized to ALA solution and 2 to vehicle. Two AKs were treated with 20% ALA, and the other 2 on the same patient were treated with vehicle. All 4 AKs were irradiated with the same dose of nonlaser blue light at the same time. A single light dose was administered to each patient by means of the DUSA BLU417 light source. The 4 target lesions were exposed to 2 J/cm2, 5 J/cm2, or 10 J/cm2 light. The 2 and 5 J/cm2 doses were achieved by means of 3 different power densities, 3 mW/cm2, 5 mW/cm2, or 10 mW/cm2. The 10 J/cm2 dose was administered at power densities of 5 and 10 mW/cm2. Assignment to each light dose was randomized. If, at week 8 after the initial treatment, the drug-treated AK did not respond, it was re-treated with 20% ALA overnight and then exposed to the same dose of blue light as was selected for the first cycle of therapy. To obtain a statistically valid sample with enough data points to look for differences in parameters at each fluence (2, 5, and 10 J/cm2), data obtained at different power densities were pooled before all comparisons were reported. Comparing the clinical response that occurred at each power density (3, 5, and 10 mW/cm2) did not reveal any significant differences in clinical response within each total light dose group (2, 5, and 10 J/cm2). ALA, vehicle, and light treatments were administered by a nonblinded investigator, and evaluation of the response of the AKs to PDT was performed by a blinded investigator. Because PDT with ALA generates a distinctive burning and stinging response, the evaluation of symptoms during and after PDT was performed by the nonblinded investigator in an attempt to maintain a nonbiased evaluation by the blinded investigator. Lesion fluorescence after drug administration was also evaluated by the nonblinded investigator. Drug application Twenty percent ALA solution or vehicle was applied to the identified target AK lesions 14 to 18 hours before fluorescence evaluation and light treatment. The 20% ALA solution was prepared by combining the contents of vials containing weighed amounts of ALA and a measured amount of vehicle, and mixing for 2 to 3 minutes until the powder dis-

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Fig 1. Distribution of fluorescence intensity after 14 to 18 hours of exposure to topically applied 20% ALA solution (black bars) or vehicle solution (gray bars). Number on top of bars indicates percentage of lesions in each group (n = 72 for both groups). Drug and vehicle fluorescences are significantly different (P < .001).

solved. The ALA solution or vehicle was applied with a cotton-tipped applicator to the AK and allowed to dry. A rim of 2 to 4 mm of perilesional skin was treated to ensure treatment of the entire target AK. This procedure was repeated for a total of 3 applications. After 14 to 18 hours, the target AKs were rinsed and allowed to air dry before fluorescence evaluation and light treatment. Fluorescence assessment Immediately before light treatment, the nonblinded investigator evaluated the fluorescence of the lesions and surrounding normal skin visually by means of a model B-100 AP ultraviolet lamp (UVP, San Gabriel, Calif) containing a Sylvania H-44 JM–100 mercury flood lamp. Fluorescence intensity was scored (0: none; 1: weak; 2: moderate; 3: intense; 4: very intense). Light treatment The DUSA BLU-417 light source is a U-shaped fluorescent light source that can administer a uniform light dose to the entire face or scalp. The peak emission occurs at 417 nm. A light detector connected as part of the DUSA-7330 dosimeter was applied to goggles that were worn by the patient during the light treatment. The light detector was held 2 inches from the surface of the light source and was used to mea-

sure the total amount of light administered as well as the instantaneous power density during therapy. Clinical assessment Safety and clinical assessments were performed at baseline, immediately after PDT, at 24 hours, at 72 hours, and at weeks 1, 4, 8, 12, and 16 after treatment. These assessments were also performed at 9 weeks only for those patients who received re-treatment at week 8. Clinical response was defined as the percentage reduction of pretreatment lesion area and rated as follows: complete response (CR; completely cleared with no evidence of adherent scale on the surface of the treated skin when palpated), partial response (PR; ≥ 50% reduction in lesion size), or no response (NR; <50% reduction in lesion size). Immediately after PDT, and at each subsequent visit, treatment sites were evaluated for objective changes in erythema, edema, wheal, vesiculation, ulceration, hemorrhage, and necrosis on a graded scale (0: none; 1: minimal; 2: moderate; 3: severe). Subjective assessment of patient discomfort from pain, burning/stinging, and itching was graded (0: none; 1: minimal; 2: moderate; 3: severe). Standard hematologic and biochemical laboratory parameters were evaluated at baseline and again at 1 week after PDT. Urine ALA was measured at baseline and 24 hours after ALA application. Safety of the treatment

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Table I. Clinical response of AKs treated with either drug or vehicle Clinical response

A. 8 wk after a single PDT treatment: Drug ALA Vehicle B. Comparison of response at 8 and 16 wk after PDT when AKs that were not CR at 8 wk were re-treated with drug and light: Weeks after ALA PDT 8 wk 16 wk

was assessed by adverse events, PDT response, and laboratory results. Statistics Differences between or within treatments were assessed by means of ridit analysis for ordinal variables and Fisher exact test for nominal variables. Spearman’s rank correlation coefficient was used to test the correlation between clinical response and fluorescence or lesion thickness grade.

RESULTS Of the 36 patients randomized into the study, 34 completed the 16 weeks. One patient voluntarily withdrew after screening, and 2 other patients were lost to follow-up after week 8. One additional patient had no efficacy data after week 4. Data for 35 patients were included in the analysis for week 8. PpIX fluorescence Visual detection of fluorescence after ALA treatment was used to verify the conversion of ALA to its active form, PpIX. After 14 to 18 hours of exposure to 20% ALA solution, red fluorescence was observed in 70 of 72 lesions (97%) when evaluated with an ultraviolet lamp, whereas vehicle alone resulted in fluorescence in 4 of 72 lesions (6%). The number and percentage of patients as a function of fluorescence intensity are shown in Fig 1. After ALA treatment, 93% of the target AK sites had moderate to very intense fluorescence. The fluorescence differences between drug- and vehicle-treated AKs were statistically significant (P < .001). After ALA treatment, the non-AK “normal” sun-damaged skin surrounding the AKs fluoresced in 47% of the lesions (34/72). These data also demonstrate that cross-contamination of the vehicletreated sites with the topically applied drug during the 14- to 18-hour pretreatment interval was not a significant problem. A total of 94% of vehicle-treated

CR No. (%)

PR No. (%)

NR No. (%)

Total

46 (66) 12 (17)

12 (17) 12 (17)

12 (17) 46 (66)

70 (100) 70 (100)

46 (66) 56 (85)

12 (17) 4 (6)

12 (17) 6 (9)

70 (100) 66 (100)

sites (68/72) had no detectable fluorescence measured just before photoactivation. Background orange fluorescence in sebaceous skin of the face was seen, as has been reported in normal individuals examined with a blue light, and this may account for the fluorescence seen in the nontreated AKs. Clinical response The clinical response of all treated AKs at week 8 and week 16 (end of study) is shown in Table I. After 8 weeks, 66% of AKs treated with a single cycle of ALA PDT were eradicated (CR), whereas only 17% of vehicle- and light-treated AKs achieved CR. These differences were statistically significant (P < .001). At 16 weeks (the end of the study) 85% of the AKs treated with ALA PDT had cleared. This increase in CR rate from 66% to 85% was statistically significant (P = .013). The increase in response of AKs to ALA PDT after 16 weeks was the result of re-treating 16 AKs with drug and light at week 8. All 44 AKs that were CR at week 8 remained CR at week 16 (see below for further discussion). This study examined the effect of treating multiple AKs (2 lesions) on the same patient with ALA PDT and vehicle followed by light. The number of patients experiencing CR of both AKs after treatment with ALA and light at week 8 and 16 is shown in Table II. Eight weeks after a single cycle of ALA PDT, 46% of the patients (16/35) had CR of both target AKs, whereas 6% of vehicle- and light-treated lesions (2/35) had CR of both AKs, a statistically significant difference (P < .001). At week 16, 76% of the patients (25/33) experienced CR of both target AKs. Re-treatment of AKs not responding to ALA PDT at the same light dose was part of the protocol. This accounts for the increase in CR rate from 46% at 8 weeks to 76% at 16 weeks where CR is defined as both target AKs on an individual patient completely clearing after PDT.

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Table II. Number of patients with 0, 1, or 2 cleared lesions after PDT No. of cleared lesions

A. 8 wk after a single PDT treatment: Drug ALA Vehicle B. Comparison of response at 8 and 16 wk after PDT when AKs that were not CR at 8 wk were re-treated with drug and light: Weeks after ALA PDT 8 16

Table III. Effect of varying light dose on the CR rate of AKs 8 weeks after a single PDT treatment Light dose

2 J/cm2 5 J/cm2 10 J/cm2

Drug

CR No. (%)

Not CR No. (%)

Drug vs vehicle

ALA Vehicle ALA Vehicle ALA Vehicle

16 (57) 8 (29) 16 (62) 3 (12) 14 (88) 1 (6)

12 (43) 20 (71) 10 (38) 23 (88) 2 (13) 15 (94)

P = .058 P < .001 P < .001

Of the 66 lesions evaluable at week 16, 44 lesions (67%) treated with ALA PDT achieved CR at week 8 and remained clear at week 16. Fifteen lesions (23%) treated with ALA PDT that had not achieved CR at 8 weeks were re-treated, and 7 of the 15 re-treated AKs (47%) resulted in CR at week 16. This resulted in an 85% CR rate (56/66) of all treated AKs evaluated at week 16 regardless of light dose. Light dose dependence of the clinical response The effect of varying the total light dose (2, 5, 10 J/cm2) on the CR rate of all AKs treated with ALA was evaluated (Table III). Eight weeks after a single PDT treatment, the response of AKs exposed to ALA and either 5 or 10 J/cm2 resulted in a statistically better response than AKs treated with the vehicle and the same dose of light (Table III). AKs treated with ALA and 2 J/cm2 were not significantly different from AKs treated with vehicle and the same dose of light (P = .058). The same data presented in the above analysis were reevaluated to examine the response of both target AKs on a single patient to ALA PDT with varying light doses. The analysis just discussed looked at the response taking each AK independent of all the other AKs (Table IV). Evaluated at 8 weeks after a sin-

0 No. (%)

1 No. (%)

2 No. (%)

Total

5 (14) 25 (71)

14 (40) 8 (23)

16 (46) 2 (6)

35 (100) 35 (100)

5 (14) 2 (6)

14 (40) 6 (18)

16 (46) 25 (76)

35 (100) 33 (100)

gle cycle of ALA PDT, AKs treated with 2 J/cm2 were not statistically different from vehicle controls after the Bonferroni correction for multiple comparisons was performed. AKs treated with 5 and 10 J/cm2 light doses have a statistically significantly better response than AKs treated with vehicle and light. At 10 J/cm2, 75% of the patients (6/8) treated with ALA PDT had CR of both AKs, whereas none of 8 patients had CR of both AKs when treated with vehicle. In summary, the data demonstrate that 5 and 10 J/cm2 is more effective than 2 J/cm2 in clearing AKs with a single cycle of ALA PDT. These data demonstrate, as expected, that the clinical response with ALA PDT depends on the dose of light administered. Lesion thickness and response The effect of lesional thickness on clinical response was evaluated. Analysis of baseline data demonstrates that the distribution of AK thickness was not statistically significantly different when ALA, vehicle, or light dose groups were compared. At week 8, the complete clinical response of drug-treated grade 1 and grade 2 AKs was better than vehicle controls of the same thickness (P < .01). Comparison of the number of grade 1 and grade 2 AKs having complete clinical response after a single treatment with ALA PDT is as follows: grade 1, 30 of 39 (77%); grade 2, 16 of 31 (52%). This was a significant difference (P = .042). Thin AKs responded better than slightly thicker grade 2 AKs on the face and scalp. Fluorescence and clinical response The relationship between complete clinical response and the presence or absence of fluorescence across all 140 treated lesions was evaluated. These data demonstrated that fluorescence and clinical response are significantly related (P < .001). These data suggest that a CR is related to the presence of fluorescence (ie, PpIX, or the active form of

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Table IV. Effect of blue light dose on the number of patients with 0, 1, or 2 cleared lesions: Comparison of ALA PDT and vehicle response 8 weeks after a single PDT treatment No. of cleared lesions

Light dose

2 J/cm2 5 J/cm2 10 J/cm2

Drug

0 No. (%)

1 No. (%)

2 No. (%)

ALA Vehicle ALA Vehicle ALA Vehicle

2 (14) 7 (50) 3 (23) 11 (85) 0 (0) 7 (88)

8 (57) 6 (43) 4 (31) 1 (8) 2 (25) 1 (13)

4 (29) 1 (7) 6 (46) 1 (8) 6 (75) 0 (0)

the drug), and less than a CR is related to the absence of fluorescence (ie, no active form of the drug). The correlation of fluorescence intensity with the magnitude of the clinical response was next examined. Fluorescence was seen in 68 of 70 drug-treated lesions (97%) and in only 4 of 70 vehicle-treated lesions (6%). There were 39 lesions with weak to moderate fluorescence after drug exposure; after a single light treatment, 74% of these lesions (29/39) with weak to moderate fluorescence had a CR, 10% had a PR (4/39), and 15% had an NR (6/39). Of 29 lesions with intense to very intense fluorescence after drug exposure, 52% (15/29) had a CR, 28% had a PR (8/29), and 21% had an NR (6/29). There was no significant relationship (P = .051) between fluorescence intensity and magnitude of clinical response (CR, PR, NR) evaluated at 8 weeks with drug-treated lesions. These data demonstrate that only a weak amount of fluorescence was necessary to generate a CR after PDT, and having intense fluorescence did not always generate a CR after PDT. Of vehicle-treated lesions, 94% (66/70) did not have detectable fluorescence. Of the target lesions that did not fluoresce after vehicle treatment, 10 of 66 (15%) had a CR, 10 of 66 (15%) had a PR, and 46 of 66 (70%) had an NR. Only 6% (4/70) had detectable fluorescence, and 2 of these had a CR. Of all the CRs occurring with vehicle, 10 of 12 (83%) did not have detectable fluorescence. These data suggest that cross-contamination of the vehicletreated AKs with drug used to treat the two other AKs was not a significant problem, because of the 12 AKs having a CR, 10 did not fluoresce. The fact that some AKs had a CR and PR after vehicle and light treatment could reflect the natural history of AKs where some AKs can spontaneously clear, rather than therapeutic effects of vehicle and light treatment.8 When the number of AKs that had a CR after ALA and the number of AKs having a CR after vehicle treatment were compared, a significant (P < .001)

Drug vs vehicle

P = .031 P = . 003 P < .001

relationship between fluorescence and the treatment that induced the CR was demonstrated. The CR that occurs with ALA PDT is associated with fluorescence; the CR associated with vehicle treatment is not associated with fluorescence. As expected, these fluorescence data suggest that the presence of active PpIX is essential for an effective PDT response. Symptoms during and after PDT with ALA Burning/stinging was associated with 89% of AKs treated with ALA during the light exposure as compared with 3% of vehicle-treated AKs. The burning/ stinging persisted above the vehicle control background for 72 hours, and was gone at 1 week (Fig 2). Most patients (51%) reported moderate burning during therapy. However, 18% of the patients reported severe burning or stinging symptoms. There was a significant decrease (P < .001) in burning/stinging when the intensity of these symptoms during light treatment was compared with the intensity immediately after light treatment. By 24 hours after PDT, 82% of AKs were reported as having no burning or stinging. All patients were able to complete the PDT treatments regardless of the reported burning or stinging symptoms. Itching was associated with 39% of the drugtreated AKs during PDT, persisted for 1 week, and was not distinguishable from vehicle control 4 weeks after light treatment (Fig 2). The presence of discomfort, manifested as pain during and after PDT of lesions with ALA or vehicle, is shown in Fig 2. Some degree of pain was reported in 43% of the drug-treated AKs during and immediately after PDT, whereas only 3% of AKs treated with vehicle experienced pain. There was no statistically significant difference in the number of painful lesions during and immediately after light exposure in ALA-treated lesions (ie, the number of painful lesions was the same during and immediately after light exposure). The pain evaluated 24 hours after light exposure in the drug-treated group decreased

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Fig 2. Subjective signs during and after ALA PDT of AKs: Percentage of ALA PDT–treated target AKs having burning/stinging (black bars), itching (gray bars), pain (white bars). *Statistically different (P < .05) from vehicle- and light-treated AKs.

significantly and was not statistically different when compared with vehicle-treated AKs. The severity of the pain associated with AKs undergoing treatment with ALA PDT and vehicle was evaluated. During PDT (during light exposure) of ALA-treated lesions 57% reported no pain, 10% minimal pain, 28% moderate pain, and 6% severe pain. Immediately after PDT (after the light exposure) 57% reported no pain, 26% minimal pain, 15% moderate pain, and 1% severe pain. Twenty-four hours after PDT 88% reported no pain, 13% minimal pain, 0% moderate pain, and 0% severe pain. All patients were able to complete all treatments regardless of the reported amount of pain. Objective physical signs after ALA PDT Starting immediately after PDT, 96% of the ALAtreated sites had erythema, compared with 15% of the vehicle controls (Fig 3). The intensity of the erythema increased significantly during the first 24 hours after PDT (P < .001) and decreased significantly in intensity during the interval from 24 to 72 hours after PDT (P < .001). The erythema persisted and was significantly more intense than the vehicle control background for 1 week (Fig 3). At 4 weeks there was no statistically significant difference in the percentage of lesions having erythema when drugand vehicle-treated AK lesional sites (14% vs 17%) were compared. It is interesting that the duration of

erythema and itching after PDT correlated and thus may be related. A transient urticarial wheal occurred in a few lesions (10%) in the ALA- and light-treated AK sites one day after PDT. This wheal was not visible immediately after PDT, was seen 24 hours after PDT, and cleared by 72 hours (Fig 3). More diffuse edema was noted in 12% of lesions immediately after PDT (Fig 3). This incidence of edema was higher than that seen with vehicle for 24 and 72 hours and cleared by 1 week after PDT. Minimal vesiculation was seen in 7 of 72 lesions (10%) treated with ALA PDT at 72 hours after PDT, and in none of 72 lesions treated with vehicle and light. These differences in vesiculation were statistically significant (P = .007). This vesiculation could represent clinical evidence of death of atypical keratinocytes in AKs treated with ALA PDT. Ulceration was reported in 1 of 72 (1%) treated with drug and light, and none of 72 treated with vehicle and light. No hemorrhage was seen in any lesions at any time during the study. Pigmentary changes after PDT A total of 7 of 66 AKs (11%) treated with ALA PDT resulted in hyperpigmentation evaluated at week 16 of the study compared with the 14% incidence (9/66) of hyperpigmentation after treating AKs with vehicle and light. Hypopigmentation evaluated at week 16

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Fig 3. Objective signs occurring after ALA PDT of AK: Percentage of ALA PDT–treated target AKs having erythema (black bars), edema (gray bars), or wheal (white bars). *Statistically different (P < .05) from vehicle- and light-treated AKs.

was seen in 1 of 66 (2%) of the drug-treated AKs and 1 of 66 (2%) of vehicle-treated AKs. The incidence of pigmentation was not statistically different when both groups were compared. Safety/adverse effects No patients were withdrawn because of an adverse event. There were no clinically significant abnormalities in laboratory tests and no significant changes from baseline of urine ALA measured at 24 hours.

DISCUSSION This is the first published investigator-blinded, randomized, vehicle-controlled study examining the effectiveness of topical ALA photodynamic therapy of AKs. The results of this study demonstrate that photodynamic therapy using topical ALA and visible, nonlaser blue light is highly effective in causing the complete clearing of multiple typical AKs on the face and scalp. Topical application of 20% ALA solution for 14 to 18 hours, followed by treatment with blue light, resulted in complete clearing of 85% of typical grade 1 and 2 AKs at the end of 16 weeks, and this was significantly better than the 25% complete clearing of AKs treated with vehicle and blue light (P < .001).

The patients’ acceptance of the treatment regimen was very good, as assessed by subjective measurements of discomfort and completion of all treatments. As expected, 89% of patients reported burning/stinging discomfort during the light exposure, which significantly decreased in intensity after the light was stopped, and cleared by 1 week after PDT. Pigmentary changes occurred after PDT in 11% of the drug-treated and 14% of the vehicle-treated lesions, a difference that is not significantly different. The results of this study are consistent with previous observations of a good clinical response of typical AKs to PDT1,3 using ALA. Most PDT studies with the PpIX-inducing drug for treatment of cutaneous lesions (eg, tumors, AKs) have used red light because of deeper light penetration in human skin. In this study, a blue light source was used to maximize activation of the PpIX in the epidermal component of AKs. Because PpIX has a maximum absorption at 410 nm (Soret band) and blue light is much more effective in activating PpIX than red light, it is not surprising that these shorter wavelengths are effective in treating superficial AKs and achieve the desired effect at low fluences of light. The choice of a blue light to photoactivate PpIX in AKs after topical ALA treatment is theoretically reasonable because AKs are a disease of the epidermis, and the blue light does not need to

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penetrate deeply to clear the pathologic changes occurring with the AKs in the epidermis. The amount of nonlaser blue light required to photoactivate the PpIX and cause complete clearing of the AKs was examined. After a single cycle of topical ALA and photoactivation, 10 J/cm2 achieved a CR rate of 88%; this was statistically better than that found with 2 J/cm2. At 2 J/cm2 two treatments with ALA and light were required to generate a CR rate that was statistically better than vehicle control. The response to 5 J/cm2 was intermediate to that of 2 and 10 J/cm2. Thus, with 20% ALA applied overnight, a maximal response (88% CR) with a single cycle of photoactivation requires more than 2 J/cm2 and is maximal at 10 J/cm2. The response rate of face/scalp AKs to topical ALA PDT is similar to that reported for topical 5fluorouracil cream, masoprocol cream, chemical peels, or liquid nitrogen therapy. Lawrence et al9 reported a 75% complete response rate of facial AKs treated with 5% fluorouracil cream twice daily and tretinoin daily for 3 weeks. Pearlman10 reported a 98% CR rate of facial AKs treated with 5% fluorouracil cream once or twice weekly for 7 weeks. Masoprocol therapy of head and neck AKs twice daily for up to 28 days resulted in a 71% decrease in total number of treated AKs.7 Therapy of facial AKs with Jessner’s solution and 35% trichloroacetic acid chemical peel resulted in a 75% CR rate evaluated 1 month after therapy.9 Lubritz and Smolewski11 reported a very limited study of aggressive liquid nitrogen therapy of AKs with a CR rate of 99% with a 1-year follow-up. A paired comparison of a single ALA PDT therapy versus topical 5% fluorouracil applied twice daily for 3 weeks as therapies of AKs on the dorsal hands was reported by Kurwa et al.12 They demonstrated that a single therapy with ALA PDT was as effective as topical fluorouracil administered over 3 weeks. In our study, therapy of face/scalp AKs with 20% ALA and light resulted in an 85% CR rate when evaluating all AKs after 2 treatments at all light doses, and an 88% CR rate with a single cycle of ALA PDT with photoactivation with the optimal light dose of 10 J/cm2. PDT with ALA may be advantageous as compared with other physician-applied AK treatments with respect to ease of treatment of multiple identifiable AKs.13,14 Application of the drug solution to multiple AKs can be done quickly and is uniform from treatment site to treatment site. After 14 to 18 hours the entire face is exposed to blue light treating only the target AKs. The main advantage is that the therapy is done after the light exposure and does not require continuous therapy with topical agents like 5% fluorouracil cream. About half of patients reported “pain” that was well tolerated during or after PDT. As expect-

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ed, 89% of patients reported burning/stinging that is typical of PDT during the light exposure component of therapy; this burning/stinging decreased significantly after stopping light exposure and cleared after 72 hours. In conclusion, PDT of multiple AKs with topical application of 20% ALA, followed by exposure to 10 J/cm2 nonlaser blue light, resulted in clearing of 88% of the AKs. It was well tolerated by the patients, and had a minimal risk of pigmentary changes. We gratefully acknowledge the assistance of Dr Mary Beth Ferdon, FASTAT, Inc. (Georgetown, SC), and Dianne Moudy, Clinical Study Administrator (UC, Irvine). REFERENCES 1. Kennedy JC, Pottier RH. Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B 1992;6:275-92. 2. Szeimies R-M, Sassy T, Landthaler M. Penetration potency of topical applied δ-aminolevulinic acid for photodynamic therapy of basal cell carcinoma. Photochem Photobiol 1994;59:73-6. 3. Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endogenous porphyrins after application of 5-aminolevulinic acid. J Am Acad Dermatol 1993;28:17-21. 4. Cairnduff F, Stringer MR, Hudson EJ, Ash DV, Drown SB. Superficial photodynamic therapy with topical 5-aminolevulinic acid for superficial primary and secondary skin cancer. Br J Cancer 1994;69:605-8. 5. Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Andersson-Engels S, et al. Photodynamic therapy of nonmelanoma malignant tumours of the skin using topical δaminolevulinic acid sensitization and laser irradiation. Br J Dermatol 1994;130:743-51. 6. Jeffes EW, McCullough JL, Weinstein GD, Fergin PE, Nelson JS, Shull TF, et al. Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid: a pilot dose-ranging Study. Arch Dermatol 1997;133:727-32. 7. Olsen EA, Abernethy L, 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 keratoses on the head and neck. J Am Acad Dermatol 1991;24:73843. 8. Marks R, Foley P, Goodman G, Hage BH, Selwood TS. Spontaneous remission of solar keratosis: the case for conservative management. Br J Dermatol 1986;115:649-55. 9. Lawrence N, Cox SE, Cockerell CJ, Freeman RG, Cruz PD. A comparison of the efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 1995;131:176-81. 10. Pearlman L. Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratosis: keratoses on the head and neck. J Am Acad Dermatol 1991;25:665-7. 11. Lubritz RR, Smolewski SS. Cryosurgery cure rate of actinic keratosis. J Am Acad Dermatol 1982;7:631-2. 12. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratosis. J Am Acad Dermatol 1999;41:414-8. 13. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981;4:633-9. 14. Dillah CJ, Jansen GT, Bradford AC. Selective cytotoxic effect of topical 5-fluorouracil. Arch Dermatol 1963;88:247-56.