Case example from the phase 3clinical trial. Pictured is a single actinic keratosis lesion before treatment(A), 24 hours after treatment (B), and 8 weeks after treatment (C).
Severity of stinging or burningdiscomfort during initial photodynamic therapy of 181 patients with topicalaminolevulinic acid at 20% wt/vol. The numbers inside the bars indicate thenumber of patients in the given discomfort category.
Piacquadio DJ, Chen DM, Farber HF, Fowler, Jr JF, Glazer SD, Goodman JJ, Hruza LL, Jeffes EWB, Ling MR, Phillips TJ, Rallis TM, Scher RK, Taylor CR, Weinstein GD. Photodynamic Therapy With Aminolevulinic Acid Topical Solution andVisible Blue Light in the Treatment of Multiple Actinic Keratoses of the Faceand ScalpInvestigator-Blinded, Phase 3, Multicenter Trials. Arch Dermatol. 2004;140(1):41-46. doi:10.1001/archderm.140.1.41
To determine the safety and efficacy of photodynamic therapy (PDT) using20% wt/vol aminolevulinic acid hydrochloride (hereinafter "ALA") and visibleblue light for the treatment of multiple actinic keratoses of the face andscalp.
Randomized, placebo-controlled, uneven parallel-group study.
Patients (N = 243) were randomized to receive vehicle or ALA followedwithin 14 to 18 hours by PDT. Follow-up visits occurred 24 hours and 1, 4,8, and 12 weeks following PDT. Target lesions remaining at week 8 were re-treated.
Main Outcome Measure
Clinical response based on lesion clearing by week 8.
Most patients in both groups had 4 to 7 lesions. Complete response ratesfor patients with 75% or more of the treated lesions clearing at weeks 8 and12 were 77% (128/166) and 89% (133/149), respectively, for the drug groupand 18% (10/55) and 13% (7/52), respectively, for the vehicle group (P<.001, Cochran-Mantel-Haenszel general associationtest). The 95% confidence interval for the difference in response rates atweek 8 was 46.9% to 71.0% and at week 12, 65.3% to 86.3%. The week 12 responserate includes 30% of patients who received a second treatment. Most patientsexperienced erythema and edema at the treated sites, which resolved or improvedwithin 1 to 4 weeks after therapy, and stinging or burning during light treatment,which decreased or resolved by 24 hours after light treatment.
Findings indicate that topical ALA PDT is an effective and safe treatmentfor multiple actinic keratoses of the face and scalp.
Actinic keratoses (AKs) are the most common epithelial precancerouslesions among light-complexioned individuals.1 Itis widely accepted that a small percentage of AKs progress to invasive squamouscell carcinoma,2,3 but some authorsbelieve that an AK actually is a squamous cell carcinomaat an early stage of development.4,5 Patientswith mutliple AKs are usually advised to seek treatment. Current modalitiesof treatment include cryosurgery, curettage, electrosurgery, excision, dermabrasion,laser surgery, and topical chemotherapy.6
Photodynamic therapy (PDT) is a cytotoxic process dependent on the simultaneouspresence of a photosensitizing agent, light, and oxygen.7 Whenaminolevulinic acid hydrochloride (hereinafter "ALA") is applied to skin,it is converted to the endogenous photosensitizer protoporphyrin IX (PpIX)in skin cells by enzymes in the heme biosynthetic pathway.8 Selectivityof photosensitization may be due in part to the ability of photodamaged orrapidly proliferating skin cells to convert more ALA to PpIX than can lessrapidly proliferating normal epidermal cells8 andmay also be due to altered cutaneous permeability caused by aberrantly differentiatedkeratinocytes. The relatively tissue-specific phototoxic effects of the topicaladministration of exogenous ALA provides a basis for using ALA-induced PpIXfor PDT.
Treatment with ALA PDT using a cream formulation and 630-nm laser lightis an effective therapy for AKs.9 Blue lighthas been shown to be more potent than red light for activating PpIX,10 and ALA PDT using a solution formulation and visibleblue light has also been shown to be an effective treatment for multiple AKs.11 The phase 3 multicenter studies described hereinevaluated the efficacy and safety of treating multiple AKs of the face andscalp with topical 20% ALA solution followed 14 to 18 hours later by photoilluminationusing a nonlaser fluorescent blue light at a dose of 10 J/cm2 deliveredat 10 mW/cm2.
This was a multicenter, investigator-blinded, randomized, vehicle-controlled,uneven parallel-group study. The results from 2 independent, identical, phase3 clinical trials are presented as a single research effort.
The study was conducted under an investigational new drug applicationand was approved by the institutional review board of each institution. Writteninformed consent was obtained from each patient before enrollment. Safetywas assessed by analyses of adverse events, PDT response, pigmentary changes,and laboratory results. Efficacy was assessed using (1) the complete responserate or clearing of individual AK lesions, (2) the percentage of patientswho experienced 75% or greater clearance of all target AKs treated (75% responserate), and (3) the percentage of patients who experienced 100% clearance ofall target AKs treated (100% response rate).
Because of the reactive nature of PDT, safety and efficacy assessmentswere performed by different investigators. Drug application and activation,light treatment, and all safety evaluations were performed by an unblindedinvestigator, and evaluation of response of AKs to treatment was performedby a blinded investigator.
To enroll, men and nonpregnant, nonlactating women had to be at least18 years old with 4 to 15 discrete target lesions on either the face or scalp.Women were postmenopausal, surgically sterile, or using a medically acceptableform of birth control and had a negative urine pregnancy test result. Majorcriteria for exclusion from the studies were (1) a history of cutaneous photosensitizationor porphyria, hypersensitivity to porphyrins, or photodermatosis; (2) useof photosensitizing drugs within a given time frame of study start; (3) veryhyperkeratotic, grade 3 (on a 0-3 scale) AK lesions among the target lesions;(4) use of topical medications such as corticosteroids, α-hydroxy acids,or retinoids on the face or scalp within 2 weeks before study entry; (5) systemicsteroid therapy within 4 weeks before study entry; (6) cryotherapy to thetarget lesions; (7) laser resurfacing, chemical peels, topical applicationof fluorouracil or masoprocol for the treatment of AKs within 2 months beforestudy entry; and (8) systemic treatment with chemotherapeutic agents, psoralens,immunotherapy, or retinoids within 2 months before study entry.
The studies were conducted at 16 sites. Randomization was performedseparately for each center in a 3:1 drug-vehicle ratio. After randomization,patients had ALA or vehicle applied by an unblinded investigator 14 to 18hours prior to light treatment. Patients returned for follow-up visits 24hours and 1, 4, 8, and 12 weeks after light treatment. Remaining target lesionswere re-treated at week 8 according to the original randomization. Re-treatedpatients returned 24 hours and 1 week after light treatment.
Efficacy assessments were performed by a blinded investigator at weeks4, 8, and 12. Laboratory tests were performed at baseline and 24 hours afterinitial light treatment and again at week 8 and 24 hours after retreatment.Events associated with phototoxic effects such as erythema, edema, stingingor burning, and changes in pigmentation were assessed at every visit by anunblinded investigator. Adverse events were assessed before, during, and aftertreatment and at each visit during the study period.
Aminolevulinic acid hydrochloride (20% wt/vol) or vehicle was appliedto individual AK lesions using a unit-dose applicator. Just prior to applicationby the unblinded investigator, the appropriate randomized test article wasthoroughly mixed for 3 minutes. The resultant topical solution was appliedto each lesion twice, and the solution was allowed to dry between applications.
Each patient was treated with visible blue light (Blu-U; DUSA PharmaceuticalsInc, Wilmington, Mass). The device was designed to provide a uniform distributionof blue light (peak output, 417 ± 5 nm) to the facial or scalp areasof a patient for 1000 seconds. The power density of light produced by thedevice was designed to be fixed at 10 mW/cm2. Final adjustmentto this value was performed by a DUSA technician at the time the device wasinstalled at the clinical trial site. A power meter was used just prior tothe treatment to verify the output (acceptable power density range, 9-11 mW/cm2). Blue-blocking goggles were worn by the patient during PDT.
Comparability of the treatment groups with respect to demographic andbaseline characteristics was assessed using a univariate analysis of variancewith treatment effect for continuous variables or the Cochran-Mantel-Haenszeltest (general association version), stratified by investigator, for discretevariables. Descriptive statistics (mean, SD, and frequency) were used to summarizedemographic and baseline characteristics for all patients.
An observed-value per-protocol analysis of the clinical response asassessed by the blinded investigator was performed at weeks 8 and 12. Patientswere excluded from the per-protocol efficacy analysis if they did not returnfor light treatment within 14 to 18 hours or if their light treatment didnot last half of the prescribed course (1000 seconds). Patients who did notmeet requirements for retreatment were excluded from visit 9 (week 12) analysis.Patients whose visits fell outside of the predefined window or had missingresponses were excluded from analysis of that visit. The percentage of individuallesions showing complete response or clearing, the percentage of patientswho experienced 75% clearance or greater of target AKs (75% response rate),and the percentage of patients who experienced 100% clearance of target AKs(100% response rate) were analyzed using the Cochran-Mantel-Haenszel testto evaluate any treatment differences.
All randomized patients who received study medication were includedin the safety analysis. The safety variables (adverse events, phototoxic reactions,pigmentation, and laboratory results) were summarized by descriptive statistics.
Results from the independent trials were similar and showed significantdifferences between treatment groups when analyzed separately and using thecombined data. Randomization was done separately for each center, and analysisof the data included stratification by investigator.
Patient demographics are summarized in Table 1. A total of 243 patients (40 women and 203 men) were randomizedto receive ALA (n = 181) or vehicle (n = 62) and blue light treatment. Therewere no statistically significant differences in patient demographics betweenthe treatment groups.
No patients had a medical history that influenced any potential effectof the treatment. Ninety-six percent (233/243) of patients completed the study.Reasons for not completing the study were patient noncompliance (4 patientsin the ALA group, 2 in the vehicle group), patient request for withdrawal(1 in the ALA group), death (1 in the ALA group), and other (1 patient ineach group).
A typical lesion clearance response is seen in Figure 1. The response rates by patient and lesion are summarizedin Table 2. The significance ofall lesion response rates was calculated with the Cochran-Mantel-Haenszelgeneral association test. The differences in response rates for patients with75% or more of their AKs cleared were significant (P<.001)at week 8 (77% [128/166] for ALA vs 18% [10/55] for vehicle) and week 12 (89%[133/149] for ALA vs 13% [7/52] for vehicle). The 95% confidence intervalfor the difference in response rates at week 8 was 46.9% to 71.0% and at week12, 65.3% to 86.3%. The complete response rates for patients with 100% ofAKs clearing at weeks 8 and 12 were 66% (109/166) and 73% (109/149), respectively,for ALA and 11% (6/55) and 8% (4/52), respectively, for vehicle (P< .001 at weeks 8 and 12). The 95% confidence interval for thedifference in response rates at week 8 was 43.8% to 65.7% and at week 12,55.3% to 75.6%. The ALA week 12 response rates include 30% (55/181) of patientswho received a second treatment.
Individual AK lesion response rates independent of how many individuallesions treated cleared at weeks 8 and 12 were 83% (1046/1258) and 91% (1019/1114),respectively, for ALA and 31% (139/455) and 25% (109/428), respectively, forvehicle (P<.001 at weeks 8 and 12). The 95% confidenceinterval for the difference in response rates at week 8 was 47.9% to 57.3%and at week 12, 61.6% to 70.4%.
Similar incidences of adverse events were seen for patients treatedwith either ALA or vehicle. However, the ALA-treated patients appeared tohave higher incidences of headache (6.6% vs 3.2%), injury (5.0% vs 1.6%),hypertension (1.7% vs 0), and skin hypertrophy (1.7% vs 0).
Of 113 adverse events, 104 (92%) were judged to be of mild or moderateseverity; 8 (7%) were rated as severe. One life-threatening adverse eventoccurred in a patient who was diagnosed with hepatocellular carcinoma andwho eventually died, an event deemed unrelated to study treatment. Ninety-sevenpercent of adverse events in the ALA group were unrelated to treatment. Adverseevents related to ALA were headache, dry skin, and conjunctivitis (Table 3). No patient withdrew from eitherstudy owing to an adverse event.
Figure 2 shows the severityof stinging or burning during initial ALA PDT treatment at 1, 6, and 11 minutesafter initiation of light treatment. The sensation of stinging or burningappeared to reach a plateau at 6 minutes into the treatment, with moderate-severediscomfort reported by at least 90% of patients treated with ALA. In 3% ofpatients, light treatment was discontinued before the full dose of light wasgiven owing to the severity of the stinging or burning. Five patients terminatedblue light treatment at fluences lower than 5 J/cm2.
The percentage of patients who reported severe levels of stinging orburning discomfort decreased by at least half immediately after light treatment(from 37% after 6 minutes of treatment to 14% immediately after treatmentcompletion), with most (81%) reporting only minimal to moderate discomfort.By 24 hours after light treatment, only 2 patients reported severe sensationsof stinging or burning, and only 28% of patients reported any discomfort.This number decreased to 7% by 1 week after light treatment.
The most common changes in lesion appearance after ALA PDT were erythemaand edema, which resolved or improved within 1 to 4 weeks after therapy. Erythemawas seen in 76% of ALA-treated patients at baseline, and increased to 93%after drug application (before light treatment). The percentage of patientswith erythema increased to 99% immediately after light treatment. One and4 weeks after light treatment, erythema was observed in 83% and 57%, respectively,of ALA-treated patients. Incidence of erythema did not increase after treatmentwith vehicle. Seventy-nine percent of patients in the vehicle group had erythematouslesions at baseline and after light treatment. One week after light treatment,65% of patients still had erythematous lesions.
One patient presented with edema at baseline. Incidence of edema inthe ALA group increased to 13% just prior to light treatment and peaked at38% twenty-four hours after light treatment. One week later, the incidenceof edema decreased to 5%. One patient in the vehicle group reported edema(at baseline only).
The most common local responses to ALA PDT were (1) crusting, observedin 49% of patients and 34% of lesions; (2) pruritis, which was observed in30% of patients and 22% of lesions; and (3) scaling, which was observed in31% of patients and 19% of lesions. Other very rare findings such as blisteror vesicle formation were reported in about 1% of all lesions treated.
Pigmentary changes of lesions, classified as hyperpigmentation or hypopigmentation,were uncommonly seen. In the ALA group, 1403 lesions were treated, and 1340were evaluated for pigmentation. In the vehicle group, 506 lesions were treated,and 483 were evaluated for pigmentation. At week 12, 95% of the ALA-treatedlesions and 90% of the vehicle-treated lesions had no pigmentary changes.Compared with baseline, there was no change in hyperpigmentation or hypopigmentationnoted throughout the study in either group. Treatment with ALA PDT using bluelight therefore does not appear to promote significant pigmentary changesin AKs.
The results of this study demonstrate that ALA PDT using blue lightis a highly effective therapy for facial and scalp AKs, with positive resultspersisting over the 12-week follow-up period. A phase 4 study with a 1-yearfollow-up period is currently under way to determine if the high responserates seen in this study are maintained over a prolonged time period.
Safety analyses revealed no treatment-emergent systemic signs or symptomsor clinically significant changes in laboratory parameters. The most commonchanges in lesion appearance were erythema and edema, with the applicationof ALA resulting in a slight increase in mild to moderate erythema and edemain the 14- to 18-hour interval prior to light treatment. Incidence of erythemaand edema peaked during the 24-hour period after light treatment, with improvementand resolution occurring within 1 to 4 weeks after therapy. Additionally,no treatment-related pigmentation effects were found. The most common adverseexperience was stinging or burning during light treatment. The stinging orburning sensation resolved in virtually all patients by 24 hours after lighttreatment. This can be significant in some patients and postmarketing experiencehas shown that the use of topical anesthetics and cooling with a fan, sprays,or other means has markedly improved the discomfort associated with the therapy.
The results of this study are consistent with previous observationsof a good clinical response of typical AKs to PDT using ALA.11- 14 Inan early study, Wolf et al13 treated a smallnumber of lesions and found that 9 of 9 completely responded to the treatment.Calzavara-Pinton14 treated 50 AKs on the face,which required an average of 2 treatments (range, 1-3), and achieved 100%apparent clinical complete responses. Of 33 AKs observed for 24 to 36 months,5 (15%) of 33 developed recurrences at 3, 6, 15, 19, and 32 months.
Most PDT studies with ALA for treatment of cutaneous lesions have usedred light because of deeper light penetration in human skin.12 Jeffeset al11 reported an 85% complete response rateafter a maximum of 2 treatments in a light dose-ranging study where a bluelight source was used. Since PpIX has a maximum absorption at 410 nm (Soretband) and blue light is approximately 50 times more effective in activatingPpIX than is red light, these shorter wavelengths were considered effectivein treating superficial AKs.10 Recently, thelong pulsed–dye laser was shown to produce results similar to incoherentbroadband lamp light in the activation of ALA for PDT of AKs,15 suggestingthat light sources already present in some dermatology practices may proveuseful for photodynamic activation.
Esters of ALA have also been synthesized and evaluated as potentialPDT drugs. A comparative study of methyl-ALA and cryotherapy was conductedby Szeimies et al.16 They performed a multicentercomparison of 193 patients (699 AKs) randomized for treatment with eitherm-ALA or cryotherapy. Overall response rates were similar between the groupsat 3 months (69% cleared for PDT and 75% for cryotherapy), but the cosmeticoutcome was superior for the PDT group.
Topical ALA PDT treatment clearly offers a significant clinical benefit,but the time required for treatment makes it a more practical considerationfor patients with multiple AKs. Anecdotally, the therapeutic benefit of ALAPDT is comparable to cryotherapy and may offer a better safety profile, butthere are no controlled comparison trials. Photodynamic therapy with ALA mayalso be better than other AK treatments with respect to ease of treatmentof multiple identifiable AKs, especially when home-based therapies such asfluorouracil are the treatments of choice.17,18 Typically,home therapies like fluorouracil require 2 to 4 weeks of treatment followedby an additional 4 to 8 weeks for healing.19 Thephysician-controlled nature of ALA PDT as well as its demonstrated safetyand efficacy and the rapid healing of erythema and edema within 1 to 4 weeksmake it an attractive alternative for both the patient and the physician.
In summary, ALA PDT offers a safe and effective therapeutic alternativefor the treatment of AK. The treatment is particularly appropriate for patientswith multiple nonhyperkeratotic AKs and offers physicians a new alternateto home application therapy for these patients.
Corresponding author and reprints: Daniel J. Piacquadio, MD, TherapeuticsInc, 4180 La Jolla Village Dr, Suite 255, La Jolla, CA 92037 (e-mail: email@example.com).
Accepted for publication September 10, 2003.
DUSA Pharmaceuticals Inc, Wilmington, Mass, provided financial supportfor this study.