ALA–PDT and MAL–PDT: What Makes Them Different

| February 27, 2009
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Therapeutic and Aesthetic Uses of Photodynamic Therapy
Part five of a five-part series

Michael H. Gold, MD
Medical Director, Gold Skin Care Center and The Laser & Rejuvenation Center, Nashville, Tennessee

Abstract
The use of photodynamic therapy has increased dramatically over the past several years. More clinicians are utilizing this therapy and additional indications for its use have become available. The photosensitizers that are utilized for this therapy differ and have been used differently over the past 10 years of our experience with photodynamic therapy. This manuscript examines the photosensitizers and the differences between them as well as reviews the literature on photosensitizers.

(J Clin Aesthetic Derm. 2009;2(2):44–47)

Parts one through four in this five-part series on photodynamic therapy (PDT) have examined PDT from many angles. Part one took a look at PDT’s varied effects in treating actinic keratoses (AKs) and the signs of photorejuvenation,1 part two examined its role in treating nonmelanoma skin cancers (NMSC) and its effects on inflammatory acne vulgaris and associated sebaceous gland disorders,[2] part three reviewed how PDT is used by clinicians in everyday medical and cosmetic dermatologic practices,[3] and part four covered its potential use as a chemopreventive agent.[4] This author hopes that through this series, clinicians will feel more at ease utilizing PDT in their own clinical practices and that in the process, they will realize how therapeutically useful PDT is and how beneficial it can be for many of their patients. This last article in the five-part series focuses on what makes aminolevulinic acid (ALA)–PDT different from methyl aminolevulinate (MAL)–PDT and how these differences may affect usage patterns among dermatologists.

ALA and MAL

PDT is a simple biochemical process that requires three basic things in order for the reaction to proceed. These include a photosensitizer, an appropriate light source, and molecular oxygen. The most common photosensitizer used in dermatology today is aminolevulinic acid (ALA). In dermatologic PDT, a 20% 5-ALA solution or its methyl ester cream (MAL) are the most common photosensitizers utilized. Actinically damaged skin cells, AKs, NMSC, and the pilosebaceous unit specifically absorb the photosensitizers.

There has been a great deal published in the literature over the past 10 years regarding PDT and its use in dermatology. From this author’s first report on its effects on photorejuvenation5 to Gold and Goldman’s first review on where we had come from with PDT to where we are going,[6] numerous reports and textbooks have looked at PDT and its beneficial uses in dermatology.

ALA–PDT utilizes 20% 5-ALA as a prodrug, which, when incorporated in the skin, becomes active in the form of protoporphyrin IX (PpIX). PpIX has a specific absorption spectrum, which is shown in Figure 1. The major absorption peak for ALA is seen in the blue light range, between 410 to 420nm. Several other, smaller absorption peaks are seen, and these have been found useful when utilizing the variety of lasers and light sources known to activate ALA, as shown in Figure 1. Numerous investigations have shown that blue light sources, along with potassium titanyl phosphate (KTP) lasers, pulsed dye lasers (PDL), and intense pulsed light (IPL) sources can be used to activate ALA. Red light, at 630nm, can also be used to activate ALA, although clinical manuscripts supporting this specific light source with ALA are not widespread in the medical literature. A US consensus paper on the proper use of ALA–PDT was published in 2006.[7]

As previously noted, MAL–PDT is the methyl ester of ALA. It also is a prodrug that, when applied to the skin, is converted to PpIX. In contrast to ALA, MAL is more lipophylic, which means it can absorb more deeply into appropriate skin cells. Most of the clinical literature for MAL has been studied with red light. As such, MAL has been evaluated predominantly as an NMSC treatment, and the medical literature supports this use. MAL has recently been evaluated with other lasers and light sources for photorejuvenation and inflammatory acne vulgaris. More research into these light sources will be forthcoming.[8–10]

The Differences Between ALA and MAL
ALA. ALA is known commercially as Levulan® Kerastick™ (DUSA Pharmaceuticals, Wilmington, Massachusetts), as shown in Figure 2. The Levulan Kerastick™ is a 20% weight/volume 5-aminolevulinic acid 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 area(s) being treated. This applicator tip is applied to a flexible glass tubing, which contains two glass vials. One of the vials contains the ALA in a powder form; the other contains the ethanol. Light manual pressure upon the glass vials in the Kerastick will break the vials allowing for mixture of the two by gentle rotation in a back and forth motion. Three minutes of mixing is recommended prior to applying the 20% 5-ALA onto the skin being treated.[6]

The primary indications for the use of Levulan in the US market include, treating AKs with or without a photorejuvenation effect, moderate-to-severe inflammatory acne vulgaris, sebaceous gland hyperplasia, and hidradenitis suppurativa. Levulan has US Food and Drug Administration (FDA) clearance for the treatment of nonhyperkeratotic AKs of the face and scalp utilizing a 14- to 18-hour drug incubation period of the ALA and the use of a blue light source for 16 minutes and 40 seconds (1,000 seconds). All other Levulan indications that have been studied are considered off-label uses of the product. Clinical trials on these other indications have shown the effectiveness of ALA–PDT in clinical practice. Now, through these clinical trials, we have learned that short-contact, full-face therapy with Levulan (usually with a one-hour drug incubation) and any of the light sources shown in Figure 1 is as efficacious as the longer drug incubation period (14–18 hours). Several researchers feel that many of the lasers and light sources are as effective as blue light.[11–12] Levulan is being studied and recommended most commonly for AKs in the US market. It is also marketed in South America and Asia as well, where its predominant use appears to be in the treatment of moderate-to-severe inflammatory acne vulgaris.

MAL. Metvix® (PhotoCure, Norway; Galderma, Ft. Worth, Texas) is the newer photosensitizer medication available to US physicians (Figure 3). It has been successfully used for a long time in Europe and other places around the world, including Australia and Brazil and some parts of Asia. Metvix has European Union (EU) clearance for the treatment of nonhyperkeratotic AKs of the face and scalp and basal cell carcinomas (BCCs) that are not suitable for conventional surgery.[8] Numerous clinical trials have been published to demonstrate the efficacy of this product in the treatment of AKs, Bowen’s Disease (squamous cell carcinoma in situ) and NMSC. These clinical trials were well performed and well designed and have shown conclusively the efficacy of MAL in the treatment of AKs, Bowen’s Disease, and NMSC. Clinical trials on the use of MAL in the treatment of skin cancers demonstrating five-year efficacy have recently been published.[8]

In the US, Metvix has received FDA approval for the treatment of nonhyperkeratotic AKs of the face and scalp. Although there is strong evidence from all of the EU clinical trials of the effectiveness of MAL–PDT in the treatment of NMSC, it did not receive FDA clearance for the treatment of these skin cancers. The red light source to be recommended for MAL has also received FDA clearance. At the time of this writing, although FDA approved for use, Metvix is not available in the US at this time; its appropriate use and market are being determined.

MAL is best utilized with a red light source at 630nm. The recommended use of MAL requires lesion preparation prior to drug incubation and light exposure. The lesions are prepared with a gentle curettage, which is followed by a three-hour drug incubation. The drug is incubated under an occlusive film or dressing to enhance the penetration of the drug. Light exposure, in the form of red light, is given after this three-hour drug incubation period. Through many clinical trials, it has been determined that two MAL–PDT treatments, given at one-week intervals, are routinely utilized in order to achieve proper response of the drug.[8]

Effects of ALA-PDT and MAL-PDT
One of the interesting effects seen with long drug incubation periods with each of the photosensitizers is an associated downtime as a result of erythema, edema, crusting, healing, and pigmentary changes, which can take up to a week or more to resolve in many individuals. Pain associated with ALA–PDT and MAL–PDT has also been reported. These effects have been reported in the literature as the “PDT effect,” a term routinely used in association with PDT and downtime.[6] PDT without a “PDT effect” is something researchers hope to achieve. The “PDT effect” is the reason there has been limited use of PDT among medical and cosmetic dermatologists. If we can lessen the “PDT effect,” more clinicians would use ALA–PDT and MAL–PDT on a more regular basis.

Several reports have tried to compare the pain and adverse events associated with these treatments. Unfortunately, these comparisons have been difficult to interpret, as clinicians use the drugs differently in clinical practice. Researchers must also compare branded drugs versus compounded drugs, as there are many differences between the two and these differences are virtually impossible to repeat and verify without further clinical analyses. In the first report comparing the therapies, Wiegell and Wulf[13] reported pain differences between MAL–PDT and ALA–PDT in acne vulgaris in a split-face study. The therapies were the same: An occluded, three-hour drug incubation with MAL and an ALA-prepared cream—not what is routinely done with Levulan and short drug incubation. The authors found effectiveness with both preparations, but significantly more pain with the ALA–PDT-treated side as compared to the MAL–PDT-treated side. In a second report, Kasche et al[14] looked at AKs treated with either ALA–PDT or MAL–PDT and noted similar results to Wiegell and Wulf—less pain associated with MAL–PDT as compared to ALA–PDT. Again, compounded ALA cream was utilized and a longer drug incubation time period than standard US therapy was used. In his commentary trying to review pain and other side effects with these drugs, Gold[15] pointed out that one must compare branded products according to the standard of care in which these products are used—one-hour drug incubation with Levulan and three-hour drug incubation under occlusion with Metvix. More pain and PDT effects are seen with Metvix when used in its current form as compared with Levulan in its standard form.

As this author has reported before, it is not possible to compare apples to oranges; you have to compare apples to apples and oranges to oranges. Therefore, if a clinician is going to use a short drug incubation for one photosensitizer, he or she should use a short drug incubation for the other photosensitizer and then compare the two. Or, one should compare standards of care for each product and determine from there which causes more adverse events.

Additionally, there have been three reports of contact allergy to Metvix, which have not been seen with Levulan.[16–18] More contact sensitivity to MAL–PDT may be evident as noted in the US pivotal trials for Metvix currently in publication.

Commentary
ALA–PDT and MAL–PDT are both successful dermatologic therapies. Short-contact, full-face therapy has been proven successful for ALA–PDT. Two treatments of MAL–PDT one week apart, utilizing a three-hour drug incubation after lesion preparation and under occlusion, has also proven to be a successful therapy. For MAL to be successful in the US market, a shorter drug incubation time needs to be studied and implemented in order to reduce the “PDT effects” that have been seen with this therapy. There is also a need for clinical trials to study the effectiveness of Metvix in short-contact mode, as has been done with Levulan, which is now the standard of care with ALA–PDT. With MAL–PDT, a variety of lasers and light sources will also have to be evaluated, as not many red light sources are available in the US market, and in light of the current economic crisis, it may not be financially feasible for many clinicians to purchase new equipment. Various light sources have been successfully utilized with ALA–PDT, and many use blue light as well as other lasers and light sources to activate ALA.

Many clinicians and patients have found PDT to be a successful therapy, as it is easy to perform in the office and is economically viable for clinical practice.

References
1.    Gold MH. The treatment of actinic keratoses and photorejuvenation utilizing photodynamic therapy. J Clin Aesthetic Dermatol. 2008;1(2):32–37.
2.    Gold MH. Lasers and light treatments for acne vulgaris—promising therapies. J Clin Aesthetic Dermatol. 2008;1(3):29–34.
3.    Gold MH. ALA–PDT in clinical practice—how one clinician performs this procedure. J Clin Aesthetic Dermatol. 2009;2(1):32–35.
4.    Gold MH. Chemoprevention utilizing ALA–PDT. J Clin Aesthetic Dermatol. 2008;1(4):26–32.
5.    Gold MH. The evolving role of aminolevulinic acid hydrochloride with photodynamic therapy in photoaging. Cutis. 2002;69(6 Suppl):8–13.
6.    Gold MH, Goldman MP. 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg. 2004;30:1077–1084.
7.    Nestor M, Gold MH, Kauvar A, et al. The use of photodynamic therapy in dermatology: results of a consensus conference. J Drugs Dermatol. 2006;5(2):140–154.
8.    Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. J Am Acad Dermatol. 2007;56(1):125–143.
9.    Zane C, Capezzera R, Sala R, Venturini M, Calzavara-Pinton P. Clinical and echographic analysis of photodynamic therapy using methylaminolevulinate as sensitizer in the treatment of photodamaged facial skin. Lasers Surg Med. 2007;39(3):203–209.
10.    Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized controlled trial. Br J Dermatol. 2006;154: 969–976.
11.    Touma D, Yaar M, Whitehead S, et al. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol. 2004;140(1): 33–40.
12.    Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic photorejuvenation. Dermatol Surg. 2002;28(8):742–744.
13.    Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate. J Am Acad Dermatol. 2006; 54(4):647–651.
14.    Kasche A, Luderschmidt S, Ring J, Hein R. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol. 2006;5(4):353–356.
15.    Gold MH. 5-Aminolevulnic acid photodynamic therapy versus methyl aminolaevulinate photodynamic therapy for inflammatory acne vulgaris. J Am Acad Dermatol. 2008;58(2):S60–S62.
16.    Wulf HC, Philipsen P. Allergic contact dermatitis to 5-aminolaevulinic acid methylester but not 5-aminolaevulinic acid after photodynamic therapy. Br J Dermatol. 2004;150:143–145.
17.    Harris MJ, Street G, Gilmour E, et al. Allergic contact dermatitis to 5-aminolevulinic acid methylester. Photoderm Photoimmunol Photomed. 2007;23:35–36.
18.    Hohwy T, Andersen KE, Sølvsten H, Sommerlund M. Allergic contact dermatitis to methyl aminolevulinate after photodynamic therapy in nine patients. Contact Dermatitis. 2007;57(5):321–323.
19.    Gold MH. Pharmoeconomic analysis of the treatment of multiple actinic keratoses. J Drugs in Dermatol. 2008;7(1):23–25.

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Category: 02-2009 (February 2009), Photdynamic Therapy, Special Series

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