With expanding indications for the use of photodynamic. Photodynamic Therapy: Indications and Treatment. Review Article

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1 Review Article Continuing Medical Education Article Skin Treatment Photodynamic Therapy: Indications and Treatment Michael H. Gold, MD Learning Objectives: The reader is presumed to have a broad understanding of aesthetic and/or dermatologic procedures and concepts. After studying this article, the participant should be able to: 1. Review the history of photodynamic therapy using 20% 5-aminolevulinic acid (ALA-PDT) and its use in modern medicine. 2. Describe clinical uses of ALA-PDT that have been studied and shown to be effective. 3. Discuss ALA-PDT pretreatment regimens. 4. Avoid potential complications of ALA-PDT treatment, and provide appropriate posttreatment instructions to patients. Physicians may earn 1 AMA PRA Category 1 Credit by successfully completing the examination based on material covered in this article. The examination begins on page 553. ASAPS members may also complete this CME examination online by logging into the ASAPS Members-Only website ( and clicking on Clinical Education in the menu bar. Photodynamic therapy using 20% 5-aminolevulinic acid (ALA-PDT) has become a standard therapy to treat a wide variety of clinical disorders, including actinic keratoses with or without photorejuvenation, moderate to severe inflammatory acne vulgaris, sebaceous gland hyperplasia, and hidradenitis suppurativa. The author reviews the evidence-based medicine that supports the use of ALA-PDT in clinical practice and discusses ways to optimize use of ALA-PDT in the clinical setting. (Aesthetic Surg J 2008;28: ) Disclosures: Dr. Gold is a consultant for, performs research for, and speaks on behalf of DUSA Pharmaceuticals, Lumenis, Aesthera, Sciton, and Cynosure. He also owns stock in DUSA Pharmaceuticals. With expanding indications for the use of photodynamic therapy (PDT) with 20% 5-aminolevulinic acid (ALA), an increasing number of clinicians have incorporated this therapy into practice. This article reviews the experience with ALA-PDT in the United States and offers recommendations for its clinical use. The history of PDT can be traced to the early 1900s, when a variety of photosensitizers were evaluated and subjected to light in an attempt to treat cutaneous disease. In 1990, Kennedy et al 1 introduced the first topical porphyrin derivative, ALA. This photosensitizer, known Dr. Gold is Assistant Clinical Professor, Division of Dermatology, Department of Medicine, Vanderbilt University Medical School and Vanderbilt University Nursing School, Nashville, TN, and Visiting Professor of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. Aesthetic Surgery Journal as a prodrug, has the ability to penetrate the stratum corneum upon delivery to the skin and be absorbed by actinically damaged skin cells, nonmelanoma skin cancer cells, and the pilosebaceous units. Kennedy et al 1 contended that once ALA is incorporated into a cell, it is converted into its active drug, protoporphyrin IX (PpIX), for a PDT reaction to occur. ALA, the natural precursor of PpIX in the heme pathway, is shown in Figure 1. PpIX has been shown to be photoactivated by a variety of lasers and light sources. Figure 2 illustrates the absorption spectrum of PpIX, with peak absorption bands in both the blue (known as the Soret band) and red light spectrums. Smaller peaks of energy may be seen in between these major absorption bands; this factor will become even more significant as ALA-PDT moves into the 21st century and a variety of lasers and light sources are used. 2 Volume 28 Number 5 September/October

2 ALA-PDT has taken 2 unique paths since its introduction. In the United States, research has centered on a 20% 5-ALA solution (Levulan Kerastick; DUSA Pharmaceuticals, Wilmington, MA) and its ability to treat actinic keratoses (AKs), moderate to severe inflammatory acne vulgaris, sebaceous gland hyperplasia (SGH), and hidradenitis suppurativa (HS), and provide photorejuvenation. In Europe and Australia, research has centered on the methyl ester derivative of 5-ALA (methyl aminolevulinate hydrochloride [MAL], sold as Metvix [PhotoCure ASA, Oslo, Norway] and Metvixia [Galderma, Dallas, TX]) in treating nonmelanoma skin cancers and AKs. Interest in photorejuvenation and inflammatory acne vulgaris treatment with methyl-ala is just beginning. 2 Because Metvix is not yet available in the US market, it will not be discussed further in this article. Recent reviews for MAL are available. 3-5 Levulan PDT is available for use in the United States and in Latin America, South America, and Asia; it is not available in Europe at this time. Levulan PDT was approved by the US Food and Drug Administration (FDA) for the treatment of nonhyperkeratotic AKs of the face and scalp, using a 14- to 18-hour drug incubation period, and subjecting the treatment site to 16 minutes and 40 seconds (1000 seconds) of blue light. All other indications for which Levulan PDT is being used are considered offlabel. Figure 1. The heme biosynthetic pathway. LEVULAN PHOTODYNAMIC THERAPY Pivotal Levulan Photodynamic Therapy Clinical Trials for Actinic Keratoses In the pivotal phase II FDA clinical trials of Levulan PDT, 39 patients with numerous nonhyperkeratotic AKs of the face and scalp received 16 minutes and 40 seconds of blue light after a 14- to 18-hour drug incubation. Pain was common during and after the treatment, as were posttreatment erythema and edema. Crust formation, lasting up to 1 week, was common. Eight weeks after the ALA-PDT treatment, 66% of the individually treated AKs resolved. For those that had not totally cleared, a second treatment was administered, and at 16 weeks posttreatment, 85% clearance of the AKs was seen. 6 A larger phase III FDA multicenter clinical trial was performed in which 243 patients were evaluated. AKs were treated individually, ALA incubation time was 14 to 18 hours, and the lesions were exposed to 16 minutes and 40 seconds of blue light. Results showed a greater than 70% complete clearance of AKs at 12 weeks. Those AKs that did not clear were once again treated; at 24 weeks, 88% of the subjects in the clinical trial had a Figure 2. The protoporphyrin IX absorption spectrum. 546 Volume 28 Number 5 September/October 2008 Aesthetic Surgery Journal

3 A B Figure 3. A, Pretreatment view of a 74-year-old woman. B, Posttreatment view demonstrates rejuvenation effect seen 5 months after 4 treatments at 1-month intervals of 20% 5-aminolevulinic acid photodynamic therapy. greater than or equal to 75% clearance of AKs as compared with 20% in the placebo arm. 7 Downtime with healing, labeled by this author as the PDT effect, and pain was experienced in most subjects in this clinical trial. A secondary endpoint was cosmetic skin improvement following the therapy; 94% of the subjects rated their cosmetic appearance as either excellent or good. This finding, an improved cosmetic appearance, began a new era of research in ALA-PDT. Open-Label Levulan Photodynamic Therapy Clinical Trials for Actinic Keratoses Alexiades-Armenakas et al 8 reported on long-pulsed dye laser (PDL) in treating AKs of the face and scalp with ALA, demonstrating its safety and efficacy. They also demonstrated that those receiving short contact ALA (3 hrs) responded similarly to those receiving longer contact drug incubation (14 to 18 hours). In 2002, Gold 9 published observations from early experiences with ALA-PDT and a blue light source, indicating that not only was there successful resolution of the treated AKs but also, surprisingly, a response was seen in contiguous areas, resulting in a rejuvenation effect (Figure 3). A PDT effect was also evident in this series of patients as they received long drug incubations. To further address the PDT effect and to make the therapy more acceptable to patients and physicians, clinical researchers began to focus on 2 aspects of treatment: (1) shorter drug incubation times and (2) treatment of the entire face, so that both clinical and subclinical AKs would be treated, providing a full photorejuvenation effect. Two important papers on PDT then appeared. The first, by Touma et al, 10 showed that a 1- hour drug incubation was as efficacious as 14 to 18 hours in improving AKs and the parameters of photodamage (ie, photorejuvenation) using a blue light source. Improvements were noted in skin sallowness, fine wrinkling, and in mottled skin hyperpigmentation. The second important clinical trial, conducted by Ruiz-Rodriquez et al, 11 reported a shorter drug incubation time (3 hours) and the use of an intense pulsed light (IPL). They treated 17 patients with ALA and an Photodynamic Therapy: Indications and Treatment IPL device, and after 2 sessions the cosmetic appearance of the patients was excellent. All of the AKs cleared with the IPL-PDT therapy, and the authors also reported an 87% improvement in skin texture, wrinkling, pigmentary changes, and telangiectasias. A series of investigator-initiated clinical trials with a variety of lasers and light sources have appeared in the literature (Table 1) The results clearly show that the use of full-face ALA application and exposure to a variety of lasers and light sources is useful in the treatment of AKs and photodamaged skin (ie, photorejuvenation). Split-Face Levulan Photodynamic Therapy Clinical Trials for Actinic Keratoses Five split-face clinical trials have been published (Table 2). The first, by Alster et al, 16 compared ALA with an IPL on one side of the face to IPL alone on the other side in 10 patients. They found that those receiving ALA-IPL improved in the parameters of photorejuvenation compared with the IPL-alone side. Key 17 used a PDL on half of the face and ALA-PDL on the other half; the ALA-PDL side showed more improvement in parameters of photorejuvenation than the PDL-alone side. Marmur et al 18 looked at a split-face ALA-IPL versus IPL alone and, through skin biopsies, evaluated ultrastructural changes within the skin. They found a greater increase in type I collagen production in those patients receiving ALA-IPL than in those receiving IPL alone. Dover et al 19 looked at an ALA-IPL split face protocol in which patients received 3 split face ALA-IPL treatments at 3-week intervals, followed by 2 additional IPL full-face treatments, and were then evaluated at 4 weeks following the last IPL treatment. They found an improvement in the global score for photoaging (80% vs 50%), mottled hyperpigmentation (95% vs 65%), and improvement in fine lines (55% vs 20%). Interestingly, in their study group of 29, there was no statistical change in tactile skin roughness or sallowness over baseline. Gold et al 20 reported on a split-face analysis using ALA-IPL on half of the face with IPL only on the other half. The protocol included 3 split-face treatments at 4- week intervals with follow-up at 1 and 3 months follow- Volume 28 Number 5 September/October

4 Table 1. Open-label clinical trials with ALA-PDT Study Light source Drug incubation Significant results Other significant notes Gold et al 12 Blue light min (10 patients) 83% AKs responded; 90% crow s feet, 100% skin roughness, 90% hyperpigmentation, 70% facial erythema Goldman et al 13 Blue light 1 hr (32 patients) 90% AKs responded; 72% 62.5% preferred skin texture, 59% pigment change ALA-PDT to cryotherapy Avram et al 14 IPL 1 hr (17 patients) 69% AKs responded; 55% telangectasia, 1 treatment with ALA-PDT/IPL 48% pigment change, 25% skin texture comparable to 5 IPL-alone treatments Alexiades- PDL 2-3 hrs (19 patients) 68% actinic chelitis (68% clearance at 12 mos) Armenakas et al 15 AKs, Actinic keratoses; ALA-PDT, 20% 5-aminolevulinic acid photodynamic therapy; IPL, intense pulsed light; PDL, pulsed dye laser. Table 2. Split-face ALA-PDT clinical trials Study Light source Drug incubation Significant results Other significant notes Alster et al 16 IPL 1 hr (10 patients) ALA-IPL side higher clinical scores for photorejuvenation Key 17 PDL 1 hr ALA-PDL more significant than PDL alone for photorejuvenation Marmur et al 18 IPL 1 hr (7 patients) Ultrastuctural analysis: increase in type I collagen more so when pretreated with ALA Dover et al 19 IPL 1 hr (20 patients) Improvement in global photoaging scale for 3 split-face treatments, ALA-IPL side (80%-50%), hyperpigmentation then 2 full-face IPLs (95%-65%), fine lines (55%-20%) Gold et al 20 IPL 1 hr (13 patients) Improvements on ALA-IPL side versus IPL alone: AKs (78%-54%), crow s feet (55%-20%), skin roughness (55%-30%), hyperpigmentation (60%-37%), facial erythema (85%-54%) AKs, Actinic keratoses; ALA-PDT, 20% 5-aminolevulinic acid photodynamic therapy; IPL, intense pulsed light; PDL, pulsed dye laser. ing the last treatment. Of the 13 subjects studied, differences were found in the ALA-IPL side versus the IPL side including improvement in AKs (78% vs 53.6%), crow s feet (55% vs 28.5%), tactile skin roughness (55% vs 29.5%), mottled hyperpigmentation (60.3% vs 37.2%), and erythema (84.6% vs 53.8%). No adverse effects were noted and no PDT effect was seen in the subjects treated, which is significant with the newer paradigm of short contact, full-face treatments with a variety of lasers and light sources (Figure 4). Recent clinical observations by Redbord et al 21 evaluated a series of ALA-PDT treatments to determine the adverse event profile. In this retrospective analysis, it was noted that only 2 of 200 treatments resulted in posttreatment photosensitivity, the most common of the adverse events (to be described later on in this article). Gold 22 recently looked at the pharmoeconomics of using ALA-PDT in a clinical practice and found it to be cost effective in treating AKs in today s health care environment. Tschen et al 23 looked at long-term follow-up in a group of patients treated with ALA-PDT; they found a reduction in expected AKs at 12 months in a group of patients with numerous AKs. ACNE VULGARIS AND RELATED DISORDERS The first report of the use of ALA-PDT for inflammatory acne vulgaris was by Hongcharu et al. 24 They used a broadband light source ( nm) and 3-hour ALA drug incubation in 22 patients with inflammatory acne vulgaris. Significant skin clearing was seen after 4 weeks, persisting for up to 20 weeks, in those undergoing multiple treatments, or 10 weeks in those undergoing a single treatment. Of note were the associated adverse events a PDT effect, consisting of an acneform folliculitis, postinflammatory hyperpigmentation, superficial peeling, and crusting. Itoh et al 25 reported on findings related to ALA and inflammatory acne vulgaris. In 2000, they reported on the use of ALA and a 635-nm pulsed excimer dye laser in what was described as an intractable case of inflammato- 548 Volume 28 Number 5 September/October 2008 Aesthetic Surgery Journal

5 A B Figure 4. A, Pretreatment view (forehead) of a 57-year-old male with actinic keratoses. B, Postreatment view 4 months after undergoing 3 20% 5-aminolevulinic acid photodynamic therapy treatments with Blue Light. ry acne vulgaris. The treated area remained disease-free for 8 months; a classic PDT effect was noted following the therapy. The group s second report in looked at a single ALA treatment in 13 patients using a polychromatic visible light ( nm). The inflammatory acne vulgaris lesions improved, and new acne vulgaris lesions were reduced through a 6-month follow-up period. A classic PDT effect, however, was once again described. Goldman 27 reported on short contact (1 hr drug incubation) with ALA and treatment with either the IPL or blue light source in treating acne vulgaris and sebaceous gland hyperplasia. PDT effects were not seen and relative clearing of the inflammatory acne vulgaris occurred within 2 to 4 weeks. Gold 28 evaluated 10 patients with moderate to severe inflammatory acne vulgaris using short contact (30-minute drug incubation) and a high-intensity blue light source. Four treatments at 1-week intervals yielded a 60% response rate (as compared with 43% with blue light alone). No PDT effects were reported. Goldman et al 29 described their experiences with blue light, with and without ALA, in a group of 22 patients. A greater response to therapy was seen in the ALA blue light group than in the blue light alone group. Again, no PDT effects were observed. Gold et al 30 reported moderate to severe inflammatory acne vulgaris responding to an IPL device with 72% clearance in 12 patients. Again, the short-contact, full-face therapies were well tolerated with no PDT effects. Taub 31 also reported success in treating inflammatory acne vulgaris with either a blue light source or an IPL, with no PDT effect. Alexiades-Armenakas 32 reported the use of the PDL and ALA in inflammatory acne vulgaris. An average drug incubation time of 45 minutes was used and, on average, 3 PDL sessions achieved skin clearing in all 14 patients involved in this clinical trial. Miller and Van Camp 33 reported on the successful use of ALA and the potassium-titanyl-phosphate laser in patients with inflammatory acne vulgaris. Photodynamic Therapy: Indications and Treatment In 2 split-face acne ALA-IPL trials, Santos et al 34 evaluated 13 patients and Rojanamatin et al 35 evaluated 14 patients, demonstrating that by using ALA with an IPL, statistical improvements in inflammatory acne vulgaris are seen with ALA-IPL compared with IPL alone. Figure 6 demonstrates use of ALA-PDT in inflammatory acne vulgaris. At the time of this writing, the use of ALA-PDT in the treatment of moderate to severe inflammatory acne vulgaris is under phase II FDA investigation with 20% ALA and a variety of lasers and light sources. Intelligence derived from this multicenter clinical trial will yield further insight for the use of ALA-PDT in acne vulgaris. From this author s perspective, ALA-PDT is useful for moderate to severe inflammatory acne vulgaris, using a variety of lasers and light sources (Figure 5). Clinical investigators have also looked at SGH and HS as possible conditions that can be successfully treated with ALA-PDT with minimal downtime. Several investigations have targeted SGH. Horio et al 36 were the first to study this and, using a slide projector as a light source, treated SGH lesions in a patient 3 times at 1-week intervals. The lesions became smaller but never resolved. Alster et al 37 reported the use of ALA-PDL on SGH lesions. One-hour drug incubation was used, and 7 patients demonstrated skin clearance with 1 treatment, while 3 others required 2 treatments. The ALA-PDL treated lesions were also found to be more improved than those lesions treated with PDL alone. Richey et al, 38 using a blue light source and 1-hour drug incubation, treated 10 patients with SGH. These patients received 3 to 6 treatments per week and were followed for 6 months after the last treatment. A 70% skin clearance rate was reported with 20% recurrence at 3 to 4 months. Gold et al 39 reported their findings with ALA, SGH, and either an IPL or blue light source. Patients received short contact (30 to 60-minute) drug incubation before treat- Volume 28 Number 5 September/October

6 A B Figure 5. A, Preoperative view of a 22-year-old woman with acne vulgaris. B, Posttreatment view 2 months following 2 20% 5-aminolevulinic acid photodynamic therapy treatments. ment with an IPL (n 5) or a blue light (n 6). Results showed SGH clearances of 55% with either therapy at the 3-month follow-up. Recalcitrant HS has also been reported to respond to ALA-PDT. Gold et al 40 reported the successful use of ALA-PDT and blue light. Strauss et al 41 failed to verify these results. Strauss reported on experiences with 4 patients with HS that received MAL under occlusion for 4 hours before local anesthesia administration; 3 patients underwent exposure to a red light source (n 3), and 1 patient received a broadband light source ( nm). The group of patients had mixed results. Only 1 patient found some success with the treatment, 1 dropped out of the trial before finishing the therapy, and the others were either unable to tolerate the treatment or experienced some worsening of the disease process. Gold et al 42 experienced different results with blue light in a group of 4 subjects with recalcitrant HS. All 4 patients were treated with short-contact (15 to 30-minute) drug incubation and exposure to a blue light source. They received either weekly or biweekly therapy for up to 4 treatments. At the 3-month follow-up period, there was a 75% to 100% resolution of disease activity. The treatments were well tolerated with no observed PDT effects. Three of the 4 patients have remained disease-free for more than 2 years, with 1 patient requiring intermittent therapy for disease control. A further study by Rivard and Ozog 43 confirmed the work of Gold et al in treatment of recalcitrant HS. Larger clinical trials are warranted to further explain the role of PDT in recalcitrant HS. USING LEVULAN PHOTODYNAMIC THERAPY IN CLINICAL PRACTICE There are no standards nor a body of empirical evidence indicating one best or single method of using ALA-PDT. Each clinician will develop guidelines and procedures to optimize the use of PDT in their own clinical practice. However, a consensus paper 44 and other articles 45,46 outline steps that one may follow when beginning PDT in the clinical setting. What follows is a description of how my clinic uses ALA-PDT. The first step is a thorough review with the patient of the risks and benefits of the procedure to be performed, explaining every detail and generating documentation (a written and signed informed consent) that this has been completed. Remember that ALA-PDT for photorejuvenation, acne vulgaris, SGH, and HS are off-label uses of ALA; this must be explained to the patient. The use of ALA for AKs, however, is approved by the FDA. The face (used as an example, because most PDT treatments are performed on the face) must be thoroughly cleansed with a mild cleanser. Next, a degreasing procedure is performed to enhance the skin s absorption of ALA. There are 2 main ways to degrease the skin: microdermabrasion or an acetone scrub. Our clinic uses an acetone scrub because it is less expensive than microdermabrasion; however, there is growing evidence that the use of microdermabrasion enhances the penetration of ALA. 47 There are options for performing microdermabrasion including standard microdermabrasion with crystals, crystal-less microdermabrasion, paddle-enhanced microdermabrasion, and microdermabrasion with iontophoresis to enhance ALA s skin penetration. If using microdermabrasion, I prefer crystal-less microdermabrasion systems, the paddle method, or the iontophoresis system. Next, the Levulan Kerastick is mixed. The Levulan Kerastick is a 20% weight/volume ALA solution with 48% alcohol. It has a special roll-on dermatologic applicator at one end to allow easy and accurate application of the medicine to the treatment area(s). The applicator tip is applied to a flexible glass tubing that contains 2 glass vials. One of the vials contains the ALA in a powder form; the other contains the ethanol. Light manual pressure on the glass vials in the Kerastick will break the vials, facilitating mixture by gentle back and forth rotation. Three minutes of mixing is recommended before the application of the 20% ALA. Once the Kerastick is prepared, it is painted onto the skin in a uniform manner, covering the forehead, cheeks, chin, and nose area. If there are AKs present, a second coat of medicine is routinely applied. The drug is then allowed to incubate on the skin. For all practical indications, drug 550 Volume 28 Number 5 September/October 2008 Aesthetic Surgery Journal

7 incubation is 1 hour for photorejuvenation and AKs, 30 to 45 minutes for inflammatory acne vulgaris, and 1 hour for SGH. For each successive treatment, drug incubation will be increased by approximately 15 to 30 minutes. The patient is now ready to receive light or laser administration. If an IPL light source is going to be used, it is recommended that the skin be cleansed once again before using the light source. One will find that the coupling medium, or gel, will not remain on the skin surface after the application of the ALA. If a blue light source or PDL is used, it is still advisable that the skin be cleansed again, although it is not mandatory. All of our treatments are carried out with the aid of cold air cooling that the patient holds and uses as needed. The treatment settings for all lasers and light sources should be the same as regular photorejuvenation settings recommended for that particular device. After the therapy is completed, there are several important steps to perform before the patient is discharged. First, any remaining ALA needs to be thoroughly removed from the skin. Many clinicians find it beneficial when performing an IPL or PDL treatment to next perform a short, 5-minute blue light quenching which will, for all practical purposes, remove any excess ALA. It may also provide the patient with additional improvement, although clinical trials evaluating this have not been conducted. Next, ice is applied onto the treated areas, which helps with any discomfort or skin burning. During this time a discussion of proper skin care and sun protection is initiated, the recommendations for which are crucial for the patient to follow in order to avoid the only real adverse effect of the procedure: phototoxicity. Phototoxicity can be minimized or completely avoided by following several very simple rules. The patient must remain out of the sun for the first 24 to 48 hours following the procedure. Sunscreen use, with a minimum sun protection factor of 30, is required, and in our office it is applied before the patient is discharged. There are many new creams and lotions under evaluation to help reduce any erythema that may be associated with lasers and light sources without the use of ALA; these are also being investigated for their potential with ALA. As noted, phototoxicity is the only major concern after an ALA-PDT procedure. By providing simple instructions to the patient, this concern has been minimized in our practice. Patients may note some desquamation of the skin after several days, but proper use of moisturizers or spray waters will minimize this effect. A phototoxic effect from ALA-PDT is shown in Figure 6. It would be nice if we could let patients know in advance the precise number of ALA-PDT treatments they will require for a given effect. However, this is not presently possible. Further studies may enable us to provide more accurate predictions. On the other hand, clinical trials do not always translate into real world experiences. Each patient must be treated based on individual presentation, and clinical trial results may then be used as general guidelines. Figure 6. A phototoxic effect from 20% 5-aminolevulinic acid photodynamic therapy is demonstrated 3 days posttreatment. Skin care is a must for patients that undergo an ALA- PDT procedure. Maintenance therapy will also be required, although no clinical trials have demonstrated when or how many treatment sessions are necessary. CONCLUSIONS ALA-PDT is a procedure that has created a new buzz in the dermatology and laser world. AKs and moderate to severe inflammatory acne vulgaris, SGH, and HS can be successfully treated with PDT using Levulan PDT and a variety of lasers and light sources. Future research endeavors will further define clinical protocols and conditions for which Levulan PDT is useful and validate new therapies to benefit our patients. REFERENCES 1. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B 1990;6: Gold MH, Goldman MP. 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30: Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, J Am Acad Dermatol 2007;56: Szeimies RM, Landthaler M, Karrer S. Non-oncologic indications for ALA-PDT. J Dermatolog Treat 2002;13(Suppl 1):S13 S Babilas P, Karrer S, Sidoroff A, Landthaler M, Szeimies RM. Photodynamic therapy in dermatology an update. Photodermatol Photoimmunol Photomed 2005;21: Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor JR. Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Dermatol 2001;45: Jeffes EW. Levulan: the first approved topical photosensitizer for the treatment of actinic keratosis. J Dermatolog Treat 2002;13(Suppl 1):S19 S Alexiades-Armenakas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic keratoses. Arch Dermatol 2003;139: Gold MH. The evolving role of aminolevulinic acid hydrochloride with photodynamic therapy in photoaging. Cutis 2002;69(6 Suppl):8 13. Photodynamic Therapy: Indications and Treatment Volume 28 Number 5 September/October

8 10. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol 2004;140: Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic photorejuvenation. Dermatol Surg 2002;28: Gold MH, Bradshaw VL, Boring MM, Bridges TM, Biron JA, Lewis TL. Treatment of sebaceous gland hyperplasia by photodynamic therapy with 5-aminolevulinic acid and a blue light source or intense pulsed light source. J Drugs Dermatol 2004;3(6 Suppl):S6 S Goldman MP, Atkin D, Kincad S. PDT/ALA in the treatment of actinic damage: real world experience. J Lasers Surg Med 2002;14(Suppl): Avram DK, Goldman MP. Effectiveness and safety of ALA-IPL in treating actinic keratoses and photodamage. J Drugs Dermatol 2004;3(1 Suppl):S36 S Alexiades-Armenakas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic chelitis. J Drugs Dermatol 2004;3: Alster TS, Tanzi EL, Welch EC. Photorejuvenation of facial skin with topical 20% 5-aminolevulinic acid and intense pulsed light treatment: a split-face comparison study. J Drugs Dermatol 2005;4: Key DJ. Aminolevulinic acid-pulsed dye laser photodynamic therapy for the treatment of photoaging. Cosmetic Dermatol 2005;18: Marmur ES, Phelps R, Goldberg DJ. Ultrastructural changes seen after ALA-IPL photorejuvenation: a pilot study. J Cosmet Laser Ther 2005;7: Dover JS, Bhatia AC, Stewart B, Arndt KA. Topical 5-aminolevulinic acid combined with intense pulsed light in the treatment of photoaging. Arch Dermatol 2005;141: Gold MH, Bradshaw VL, Boring MM, Bridges TM, Biron JA. Split-face comparison of photodynamic therapy with 5-aminolevulinic acid and intense pulsed light versus intense pulsed light alone for photodamage. Dermatol Surg 2006;32: Redbord KP, Hanke CW. Topical photodynamic therapy for dermatologic disorders: results and complications. J Drugs Dermatol 2007;12: Gold MH. Pharmacoeconomic analysis of the treatment of multiple actinic keratoses. J Drugs Dermatol 2008;7: Tschen EH, Wong DS, Pariser DM, Dunlap FE, Houlihan A, Ferdon MB, et al. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol 2006;155: Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000;115: Itoh Y, Ninomiya Y, Tajima S, Ishibashi A. Photodynamic therapy for acne vulgaris with topical 5-aminolevulinic acid. Arch Dermatol 2000;136: Itoh Y, Ninomiya Y, Tajima S, Ishibashi A. Photodynamic therapy of acne vulgaris with topical delta-aminolevulinic acid and incoherent light in Japanese patients. Br J Dermatol 2001;144: Goldman MP. Using 5-aminolevulinic acid to treat acne and sebaceous hyperplasia. Cosmetic Dermatol 2003;16: Gold MH. The utilization of ALA-PDT and a new photoclearing device for the treatment of severe inflammatory acne vulgaris results of an initial clinical trial. J Lasers Surg Med 2003;15(Suppl): Goldman MP, Boyce S. A single-center study of aminolevulinic acid and 417 nm photodynamic therapy in the treatment of moderate to severe acne vulgaris. J Drugs Dermatol 2003;2: Gold MH, Bradshaw VL, Borin MM, Bridges TM, Biron JA, Carter LN. The use of a novel intense pulsed light and heat source and ALA-PDT in the treatment of moderate to severe inflammatory acne vulgaris. J Drugs Dermatol 2004;3(6 Suppl):S15 S Taub AF. Photodynamic therapy for the treatment of acne: a pilot study. J Drugs Dermatol 2004;3(6 Suppl):S10 S Alexiades-Armenakas MR. Long pulsed dye laser-mediated photodynamic therapy combined with topical therapy for mild-to-severe comedonal, inflammatory and cystic acne. J Drugs Dermatol 2006;5: Miller A, Van Camp A. Treatment of cane vulgaris with photodynamic therapy: the use of aminolevulinic acid and green light. Cosmetic Dermatol 2006;19: Santos AV, Belo VG, Santos G. Effectiveness of photodynamic therapy with topical 5-aminolevulinic acid and intense pulsed light versus intense pulsed light along in the treatment of acne vulgaris: comparative study. Dermatol Surg 2005;31: Rojanamatin J, Choawawanich P. Treatment of inflammatory facial acne vulgaris with intense pulsed light (IPL) and short contact of topical 5- aminolevulinc acid (ALA): a pilot study. Dermatol Surg 2006;32: Horio T, Horio O, Miyauchi-Hashimoto H, Ohnuki M, Isei T. Photodynamic therapy of sebaceous hyperplasia with topical 5-aminolevulinic acid and slide projector. Br J Dermatol 2003;148: Alster T, Tanzi E. Photodynamic therapy with topical aminolevulinic acid and pulsed dye laser irradiation for sebaceous hyperplasia. J Drugs Dermatol 2003;2: Richey DF, Hopson B. Treatment of sebaceous hyperplasia by photodynamic therapy. Cosmetic Dermatol 2004;17: Gold MH, Bradshaw VL, Boring MM, Bridges TM, Biron JA, Lewis TL. Treatment of sebaceous hyperplasia by photodynamic therapy with 5- aminolevulinic acid and a blue light source or intense pulsed light source. J Drugs Dermatol 2004;3(6 Suppl):S6 S Gold MH, Bridges TM, Bradshaw VL, Boring M. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol 2004;3(1 Suppl):S32 S Strauss RM, Pollock B, Stables GI, Goulden V, Cunliffe WJ. Photodynamic therapy using aminolevulinic acid does not lead to clinical improvement in hidradenitis suppurativa. Br J Dermatol 2005;152: Gold MH, Bridges TM, Bradshaw VL, Boring M. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol 2004;3(1 Suppl):S32 S Rivard J, Ozog D. Henry Ford Hospital dermatology experience with Levulan Kerastick and blue light photodynamic therapy. J Drugs Dermatol 2006;5: Nestor MS, Gold MH, Kauvar AN, Taub AF, Geronemus RG, Ritvo EC, et al. The use of photodynamic therapy in dermatology: results of a consensus conference. J Drugs Dermatol 2006;5: Gold, MH, Nestor MS. Current treatments of actinic keratosis. J Drugs Dermatol 2006;5(2 Suppl): Gold MH, Biron JA, Boring M, Bridges TM, Bradshaw VL. Treatment of moderate to severe inflammatory acne vulgaris: photodynamic therapy with 5-aminolevulinic acid and a novel advanced fluorescence technology pulsed light source. J Drugs Dermatol 2007;6: Fang JY, Lee WR, Shen SC, Fang YP, Hu CH. Enhancement of topical 5- aminolaevulinic acid delivery by erbium: YAG laser and microdermabrasion: a comparison with iontophoresis and electroporation. Br J Dermatol 2004;151: Accepted for publication August 4, Reprint requests: Michael H. Gold, MD, 2000 Richard Jones Rd., Ste. 220, 221, 223, 230, Nashville, TN sduncan@goldskincare.com. Copyright 2008 by The American Society for Aesthetic Plastic Surgery, Inc X/$34.00 doi: /j.asj Volume 28 Number 5 September/October 2008 Aesthetic Surgery Journal