Photodynamic Therapy for the Dermatologist

Updated: Jul 15, 2016
  • Author: Jaggi Rao, MD, FRCPC; Chief Editor: William D James, MD  more...
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Overview

Overview

Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light, and oxygen for the treatment of malignant or benign diseases. Photodynamic therapy is a 2-step procedure. In the first step, the photosensitizer is administered to the patient by one of several routes (eg, topical, oral, intravenous), and it is allowed to be taken up by the target cells. The second step involves the activation of the photosensitizer in the presence of oxygen with a specific wavelength of light directed toward the target tissue. Because the photosensitizer is preferentially absorbed by hyperproliferative tissue and the light source is directly targeted on the lesional tissue, photodynamic therapy achieves dual selectivity, minimizing damage to adjacent healthy structures.

This article provides an update on photodynamic therapy for the practicing dermatologist by discussing each of the essential components in sequence: mechanisms of action, common photosensitizers, typical light sources, and applications. Although various photodynamic therapy photosensitizers have been studied in dermatology, this article focuses on the uses of topically applied aminolevulinic acid (ALA) and methylaminolevulinate (MAL).

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Mechanisms of Actions

Most cells of the human body can transform ALA or MAL into porphyrins. However, significant differences exist in porphyrin accumulation between various tissues and cell types. After the application of MAL or ALA to human skin, porphyrins accumulate mostly in sebaceous glands and the epidermis. Neoplastic cells accumulate more porphyrins than normal cells, which has prompted the development of ALA and MAL photodynamic therapy (PDT) for the treatment of actinic keratoses (AKs), Bowen disease, and basal cell carcinoma (BCC).

Light at a wavelength corresponding to a peak of the porphyrin excitation spectrum in tissues is used to most efficiently generate a therapeutic effect. The Soret band (approximately 405-420 nm) is the most important excitation peak of protoporphyrin IX and is included in the spectral output of the US Food and Drug Administration (FDA)–approved Blu-U device, which is used with ALA. Another peak in the excitation spectrum of porphyrins includes a red peak at approximately 635 nm, which is targeted by different devices, including those approved to be used with MAL.

Following blue or red light activation, porphyrins are excited to a higher energy triplet state, which can either emit light (fluorescence) or generate reactive oxygen species, such as singlet oxygen or free radicals. The generation of singlet oxygen species, labeled type 2 photochemical reactions, are believed to predominate in photodynamic therapy. Because singlet oxygen does not travel very far within a cell, the molecular effects are influenced by the intracellular localization of the photosensitizer at the time of light exposure. Porphyrins derived from ALA are mainly localized in the vicinity of mitochondria, which can lead to apoptosis or necrosis of malignant cells upon light exposure. Both phenomena have been shown to be induced following ALA photodynamic therapy.

For the treatment of acne, preferential targeting of sebaceous glands and Propionibacterium acnes reduction are believed to be the main mechanisms involved. Because P acnes has been shown to naturally accumulate porphyrins, blue or red light alone can also have a direct therapeutic photodynamic effect on the bacteria. The exact mechanisms involved in ALA photodynamic therapy for the treatment of photoaging are not well known, but increased collagen synthesis has been demonstrated following ALA photodynamic therapy.

Beyond direct phototoxic effects on target tissue, photodynamic therapy with various photosensitizers has been shown to modify cytokine expression and induce immune-specific responses. Immunologic effects include the production of interleukin 1-beta, interleukin 2, tumor necrosis factor-alpha, and granulocyte colony-stimulating factor. Photodynamic therapy generally has a low potential for causing DNA damage, mutations, and carcinogenesis.

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Photosensitizers

The most commonly used photosensitizers in photodynamic therapy (PDT) are ALA and MAL. Both ALA and MAL are approved in several countries, including the United States, for the treatment of AKs only. However, off-label uses such as the treatment of BCC, photoaging, and acne vulgaris are common. Each photosensitizer is discussed below.

5-Aminolevulinic acid

ALA is currently available in a prepackaged plastic tube containing 2 sealed glass ampules, 1 with the ALA powder and the other with the hydroalcoholic solution (Levulan). The vehicle ampule contains 1.5 mL of solution composed of ethanol (48% v/v), water, laureth-4, isopropyl alcohol, and polyethylene glycol. The other ampule contains 354 mg of ALA hydrochloric acid as a dry powder. The applicator tube is enclosed in a protective cardboard sleeve with a cotton applicator. These Levulan Kerasticks are available in boxes of 6.

The topical solution (final ALA concentration of 20%) must be prepared just prior to application by breaking the glass ampules with gentle pressure and subsequently mixing the contents by shaking the applicator. Care must be taken to break the 2 ampules well before application.

The only approved indication for ALA (ie, in the United States and Canada) is for the treatment of hypertrophic AKs of the face and scalp.

Methylaminolevulinate

MAL is available in a cream containing 168 mg/g of MAL (final MAL concentration of 16.8%), glyceryl monostearate, cetostearyl alcohol, polyoxyl stearate, methylparaben, propylparaben, disodium edetate, glycerin, white petrolatum, cholesterol, isopropyl myristate, refined peanut oil, refined almond oil, oleyl alcohol, and purified water. The trade name for this product is Metvix, except in the United States, where it is called Metvixia.

MAL cream is packaged in an aluminium tube containing 2 g of cream. A tube should be used within 1 week after opening. MAL cream should be stored at 2-8°C (35.6-46.4°).

MAL is currently approved in the United States for the treatment of nonhyperkeratotic AKs of the face and scalp in immunocompetent patients. MAL is also approved in several European countries, New Zealand, and Australia for superficial and/or nodular BCC unsuitable for other available therapies because of possible treatment-related morbidity or a potentially poor cosmetic outcome. MAL has also been approved in Europe for squamous cell carcinoma (SCC) in situ (Bowen disease) when surgical excision is considered less appropriate. The exact indication varies according to country.

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Light Sources

Any light source, either laser or nonlaser, with suitable spectral characteristics and a high output at an absorption maximum of the photosensitizer can be used for photodynamic therapy (PDT).

Lasers

The purpose of lasers in photodynamic therapy is to initiate photochemical reactions in contradistinction to their photothermal or photomechanical effects, as are seen in other dermatologic uses. Almost any laser with an output wavelength within the visible spectrum (400-800 nm) may be used to activate ALA and MAL, although efficiency may be compromised if the output wavelength does not approximate the spectral absorption peak of the photosensitizer.

Laser photodynamic therapy has many advantages. First, the monochromaticity of lasers provides maximum effectiveness if the wavelength of the laser corresponds with the peak absorption of the photosensitizer. Second, lasers can produce high irradiance to minimize the therapeutic exposure time. Finally, lasers can be readily coupled to fiberoptics, enabling light delivery to any organ, such as the bladder, gastrointestinal tract, or lungs. On the other hand, lasers in photodynamic therapy are not without their limitations. The lasers are relatively expensive, they require special maintenance, and, when coupled with fiberoptics, they may only be used only small skin lesions.

Noncoherent light sources

In the treatment of large skin lesions, noncoherent light sources are superior to laser systems because of their large illumination fields. Other advantages of noncoherent light sources are their low cost, smaller size, and ready availability. Additionally, polychromatic light sources allow the use of different photosensitizers with different absorption maxima. Given the right dose of drug and light, noncoherent light sources appear to be every bit as effective as laser sources.

Light sources for ALA and MAL

In current dermatologic use, the most widely accepted application of ALA photodynamic therapy is with blue light for the treatment of AKs. FDA-approved blue light sources include the Blu-U and ClearLight systems.

MAL photodynamic therapy involves exposure to 37 J/cm2 or 75 J/cm2 of red light using the Aktilite or the Curelight device, respectively. Aktilite is the most widely used device in Europe and is now approved in the United States.

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Uses of Photodynamic Therapy in Dermatology

The only FDA-approved indication for ALA photodynamic therapy (PDT) and MAL photodynamic therapy in dermatology is currently the treatment of AKs. Common off-label uses include the treatment of BCC, photoaging, acne vulgaris, and Bowen disease. Less common off-label indications are possible.

Also see the clinical guidelines from the European Dermatology Forum: European Dermatology Forum Guidelines on topical photodynamic therapy. [1]

Actinic keratoses  [2, 3, 4, 5, 6, 7, 8]

Both ALA and MAL are approved in several countries, including the United States (by the FDA), for the treatment of AK. In the FDA-approved protocol, ALA is to be applied on AKs only, followed 14-18 hours later by 10 J/cm2 of blue light exposure using the Blu-U device. In phase 3 studies, lesions of 243 patients were treated once with ALA photodynamic therapy and were re-treated at 8 weeks if they did not show a complete response. The complete clinical response of individual lesions at week 12 was 91%, with just one ALA photodynamic therapy session. The percentage of patients who had a complete response with all lesions was 73% at week 12. However, in clinical practice, most physicians are currently using shorter (30-90 min) incubation times for the treatment of AK. This short incubation period has not yet been approved by regulatory authorities.

Although the FDA-approved protocol involves the application of ALA only on individual lesions, many physicians are now using broad applications on facial areas where multiple ill-defined AKs or concomitant photoaging is present. This has the theoretical advantage of treating subclinical precancerous lesions. In studies using the hairless mouse as a model, [9] multiple broad-area ALA and MAL applications followed by light exposure have been shown to delay the appearance of AK and SCC. If broad-area application is used, clinicians should be careful when using intervals of longer than 1 hour between drug application and light exposure. The phototoxic reaction (erythema, crusting) observed after ALA and MAL is significantly stronger with longer exposure time.

Physicians are also currently using light sources other than the FDA-approved Blu-U for the treatment of AK. These include intense pulsed light and pulse dye laser. Limited data are available on the efficacy of these light sources combined with ALA for the treatment of AK.

For the treatment of AK with MAL, the cream is applied on lesions following skin preparation. Skin preparation consists of removal of the crusts or hyperkeratotic portion of the AK with a curette, which probably enhances MAL penetration. MAL is then applied under occlusion for a period of 3 hours, followed by exposure to 37 J/cm2 or 75 J/cm2 of red light using the Aktilite or the Curelight device, respectively. The European labeling suggests using a single MAL photodynamic therapy session, although this can be repeated 3 months later for lesions that did not completely respond. The FDA-approved protocol suggests using 2 MAL photodynamic therapy sessions conducted 7 days apart.

A multicenter randomized study comparing the efficacy of 2 MAL photodynamic therapy treatments 7 days apart with a single treatment, followed by retreatment at 3 months for lesions that did not exhibit a complete response, showed that both regimens were equally effective. However, subanalysis of the data suggested that a single session (without retreatment) may not be sufficient for AKs that are of moderate thickness.

See the image below.

Actinic keratosis. Courtesy of Hon Pak, MD. Actinic keratosis. Courtesy of Hon Pak, MD.

Basal cell carcinoma

A number of small studies have been published using ALA photodynamic therapy for the treatment of BCC. However, these studies used varying ALA formulations, concentrations, penetration enhancers, light sources, and time between ALA application and light exposure. These studies have shown short-term complete response rates ranging from 59-92% and recurrence rates ranging from 5-44%, with a tendency towards lower clearance rates for nodular BCC. These variations in response are probably related to the different protocols and techniques used. Therefore, clinicians should be cautious when using ALA for the treatment of BCC, especially nodular BCC, given that this is not an approved indication, with no large long-term studies on the efficacy of this treatment with the currently available ALA formulation.

Only MAL has been studied with standardized protocols in phase 3 multicenter trials for the treatment of BCC. Both the Curelight and the Aktilite devices have been used in these studies. In all these studies, a gentle curettage was performed to remove crusts before MAL application.

Studies show histological cure rates at 3 months to be 85% for superficial BCC and 75% for nodular BCC. At 24 months after treatment, lesion recurrence rates (recurrence in lesions that initially showed a complete response) have been reported to be 18%. Five-year follow-up data recently presented at meetings show that most recurrences following MAL photodynamic therapy for superficial or nodular BCC occur during the first 2 years after photodynamic therapy. A consistent finding in MAL photodynamic therapy studies for BCC is that the cosmetic outcome has been shown to be superior to surgery or cryotherapy.

Also see the clinical guidelines from the European Dermatology Forum: Guideline on the Treatment of Basal Cell Carcinoma. [10]

See the image below.

Basal cell carcinoma. Basal cell carcinoma.

Photoaging

Large-surface ALA photodynamic therapy with the Blu-U or intense pulsed light devices for the treatment of photoaging is not currently approved by the FDA, but it is widely used by dermatologists. At present, the optimum parameters for the treatment of photoaging with ALA are unknown. Variations in the number of sessions and in the device, filters, fluence, irradiance, and frequency used could all have a significant impact on efficacy. MAL also has the potential to improve photoaging; however, MAL photodynamic therapy for photoaging is only starting to be used in Europe and efficacy data are lacking.

See the image below.

Female patient with advanced dermatoheliosis (phot Female patient with advanced dermatoheliosis (photoaging) and skin laxity.

Acne vulgaris  [11, 12, 13, 14, 15]

ALA photodynamic therapy is currently used off-label for the treatment of acne. Significant clinical improvement and a decrease in sebum production and sebaceous gland size have been shown posttreatment. Histological analysis showed destruction of sebaceous glands, which suggests that this therapy has the potential for long-term improvement of acne. Additional small studies using various light sources, including the Blu-U and intense pulse light, have also been published and suggest that ALA photodynamic therapy has efficacy for the treatment of acne.

Physicians currently using ALA photodynamic therapy for the treatment of acne use a short incubation time of 30-60 minutes followed by light exposure, mostly from a Blu-U or an intense pulse light device. Pulse dye lasers can also be used, although the spectral output of the pulse dye laser is not ideal to match the excitation spectrum of protoporphyrin IX. Multiple sessions may provide a better improvement; however, the exact frequency and number of sessions required to optimize the treatment is currently unknown.

The importance of using red versus blue light has not been thoroughly studied, but given that sebaceous glands are often located in the mid dermis, red light might be a better choice to target these glands.

See the image below.

Acne vulgaris. Acne vulgaris.

Bowen disease  [16, 17, 18, 19, 20]

Both ALA and MAL have been shown to induce good clinical responses in persons with Bowen disease (SCC in situ). MAL has been approved in Europe for the treatment of Bowen disease when surgical excision is considered less appropriate. Bowen disease might be one of the best clinical indications for photodynamic therapy because the lesions often are large and the surgical approach may result in extensive scarring.

See the image below.

Bowen disease, right temple. Bowen disease, right temple.

Other applications

ALA photodynamic therapy using a 595-nm pulse dye laser has been reported to induce a better response than pulse dye laser therapy alone in the treatment of sebaceous hyperplasia in a pilot study with 10 patients. A number of anecdotal descriptions of using ALA photodynamic therapy for various other skin diseases have also been reported, including actinic cheilitis, [21] verruca planae, [22] and condylomata acuminata [23] ; however, these are beyond the scope of this article.

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Adverse Effects and Contraindications

Phototoxic reactions – Desired and excessive

A burning sensation or, less commonly, pruritus, is observed during light exposure after ALA or MAL application for photodynamic therapy (PDT). These sensations usually decrease rapidly once the light source is paused or exposure is terminated. A phototoxic reaction on AKs and BCC is characterized by erythema, edema, crusting, vesiculation, or erosion in most patients. This is considered a normal and desirable reaction to achieve clearance of these lesions.

When ALA photodynamic therapy is used on large skin surfaces with shorter application times, this phototoxic reaction is less intense. It typically lasts only a few days but sometimes can last 7-10 days. Sometimes, edema may last up to 1 week and erythema may last up to 2 weeks. Erythema and edema are often followed by peeling. The severity of this phototoxic reaction is variable and can sometimes be severe and associated with a burning sensation, pain, crusting, vesicles, and intense peeling. This phototoxic reaction is greatly enhanced and can be quite severe if patients expose themselves to the sun or to powerful artificial lights during the first 2 days after topical application.

Pigmentary abnormalities and hypersensitivity reactions

Hyperpigmentation is sometimes seen after photodynamic therapy. It tends to fade over a few months. Hypopigmentation at treated sites has also been reported. Cases of allergic contact dermatitis and urticaria to MAL have been reported.

Systemic absorption potential

Extensive topical application of ALA could theoretically lead to systemic absorption. In clinical trials, ALA has been given orally at doses of up to 120 mg/kg. Cases of increased liver enzyme levels have been reported in patients treated with oral doses of ALA of 30 mg/kg or more. If all the ALA contained in a Kerastick is completely absorbed (which could only happen if the drug is ingested), the total dose of ALA absorbed would be approximately 5 mg/kg for a 70-kg person.

Precautions

ALA and MAL cream should only be administered in the presence of a physician who is knowledgeable in the use of photodynamic therapy. These products should only be used in the office or clinic setting and should never be used as self-applied treatments by patients. As a general precaution, sun exposure on the treated lesion sites and peripheral skin should be avoided for at least 48 hours following topical application of ALA and MAL.

Direct eye contact with ALA or MAL should be avoided. Individual cases of increased phototoxic reactions following ALA photodynamic therapy performed on patients using topical retinoids have been reported to the manufacturer.

Contraindications

ALA is contraindicated in patients with cutaneous sensitivity at 400-450 nm, porphyria, known allergies to porphyrins, or known sensitivity to any component of the ALA solution. In addition, caution should be used in patients sensitive to other wavelengths, given that some clinicians are using ALA with a light source outside the 400- to 450-nm range.

MAL is contraindicated in persons with porphyria, cutaneous hypersensitivity, allergy to porphyrins, or known sensitivity to any component of the cream. Importantly, note that the cream contains peanut and almond oils.

ALA and MAL have not been studied for the treatment of morpheaform and pigmented BCC; therefore, photodynamic therapy should be considered contraindicated for these lesions.

Both ALA and MAL are in FDA pregnancy category C; reproduction studies have not been performed on animals.

ALA and MAL are not approved for use in children. The use of photodynamic therapy with ALA and MAL might benefit children with basal cell nevus syndrome, but experience with treating patients younger than 8 years is very limited.

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Perspective and Summary

Photodynamic therapy (PDT) represents another potential and effective modality for the treatment of superficial skin growths, especially AKs, Bowen disease, superficial BCC, and chronic inflammatory diseases such as psoriasis. [24, 25, 26, 27, 28, 29, 30, 31] At present, topical ALA and MAL are the most promising photodynamic therapy agents for many dermatologic uses.

The major limitation of topical photodynamic therapy is its depth of treatment, which appears to be mainly the result of the failure to achieve adequate drug penetration, rather than light penetration. Greater uptake and a greater effective depth for photodynamic therapy could be obtained by increasing the application or occlusion times or by adding penetration enhancers (eg, acetone scrubs). Iontophoresis and electroporation can be used to drive ALA, a charged molecule, into the skin. As improved photosensitizers and less expensive light sources are developed, photodynamic therapy will undoubtedly become a more viable alternative for the treatment of a variety of dermatologic disorders.

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Therapeutic Guidelines for AK Treatment

General considerations

The details, risks, and benefits of photodynamic therapy (PDT) must be discussed with the potential patient. Alternative treatments for AK, including cryotherapy, 5-fluorouracil, and imiquimod, should be discussed. Obtaining signed informed consent is recommended. The individual variability of phototoxic reactions seen following photodynamic therapy and the possibility of a severe phototoxic reaction (with erythema, a burning sensation, crusting, and vesicles) should be discussed in advance.

Patients should be thoroughly questioned concerning the use of any prescription drugs, over-the-counter medications, or herbal products and regarding any procedures that could increase the photosensitivity or penetration of MAL or ALA. Patients should consult with their physician before starting any new topical or systemic treatment in the week following the photodynamic therapy session. Any lesion suggestive of BCC, SCC, or melanoma should undergo biopsy or should be excised before ALA or MAL photodynamic therapy because treatment limited to the superficial portion of these malignancies could lead to deep recurrence.

Although chemical sunscreening agents are cosmetically appealing, they do not afford protection against visible light photosensitivity due to the presence of porphyrins in the skin. However, physical sunscreening agents may provide a certain degree of protection depending on the particle size of the physical agent. A sunscreen with physical sunscreening agents may be applied to the face before the patient leaves the clinic and for 2 days following ALA photodynamic therapy. Patients should also use a broad-spectrum sunscreen during the weeks after photodynamic therapy to prevent possible hyperpigmentation, especially if erythema and crusting are present following the procedure.

Aminolevulinic acid photodynamic therapy

Therapeutic guidelines for ALA photodynamic therapy using the Blu-U photodynamic therapy device

Pretreat the area where ALA will be applied with rigorous scrubbing, using acetone to degrease and reduce surface keratin, especially if a short incubation time is used.

Prepare the Kerastick for application. Hold the Kerastick so that the applicator cap is pointing up, then crush the bottom ampule containing the solution vehicle by applying finger pressure to the cardboard sleeve approximately 2 cm from the bottom end. This should be followed by crushing the top ampule containing the ALA powder by applying finger pressure to the cardboard sleeve just below the applicator cap. Crushing the applicator can then be continued downward in similar fashion until the fingers reach the original crushed position at the bottom of the applicator. The now-crushed Kerastick should be held between the thumb and forefinger and shaken gently, away from the face, for at least 3 minutes to completely dissolve the ALA powder in the solution vehicle. Following solution admixture, the cap of the Levulan Kerastick must be removed and the dry applicator tip should be dabbed on a gauze pad or a rubber glove until uniformly wet with solution.

The solution should be applied directly to the target lesions by dabbing gently with the wet applicator tip of the Kerastick. Enough solution should be applied to uniformly wet the lesion surface, including the edges, without allowing the solution to run or drip. Once the initial solution application has dried, ALA should be applied again in the same manner. Although the ALA product monograph describes application to individual lesions of AK, a common practice is to apply the solution to active lesions and to sun-exposed facial skin prone to developing lesions. It should not be applied to the periorbital area or allowed to contact ocular or mucosal surfaces. Because of the short-term stability of ALA solutions, the Kerastick must be used immediately following preparation.

Patients should stay inside and avoid exposure to sunlight, bright artificial lights, or cold between ALA application and light exposure.

The product monograph suggests light exposure 14-18 hours after ALA application. If ALA has been applied to large areas of sun-exposed skin, light exposure should occur 30 minutes to 2 hours after ALA application to avoid intense widespread phototoxic reactions. Patients who have never been treated with ALA photodynamic therapy can be started with a 30- to 60-minute incubation time if ALA is applied to broad areas. The incubation time can be adjusted at the following session according to the intensity of the phototoxic reaction and the clinical response of the AK lesions treated.

Immediately before light illumination, the area where ALA was applied should be rinsed with water and patted dry. Blue-blocking protective eyewear should be worn by the patient, the operator, and any other person in the treatment room. Using the Blu-U device, patients are exposed to 10 J/cm2, which corresponds to 16 minutes 40 seconds, provided the patient's lesions are within 2-4 inches of the device.

After light treatment, patients should not expose themselves to sunlight or intense light for at least 48 hours. Noncompliance can result in a severe phototoxic reaction.

Treated lesions that have not completely resolved after 8 weeks may be treated a second time with ALA photodynamic therapy. Regular patient follow-up is recommended.

Methylaminolevulinate photodynamic therapy

Therapeutic guidelines for MAL photodynamic therapy using the Aktilite photodynamic therapy device

Before applying MAL cream, the surface of AK lesions should be gently debrided with a dermatological curette to remove hyperkeratotic scales and crusts.

A layer of MAL cream (approximately 1 mm thick) should be applied to the lesion and to the surrounding 5 mm of normal skin using a spatula. Ideally, nitrile gloves should be worn when applying and removing MAL cream. Vinyl and latex gloves do not provide adequate protection when using this product. The treated area should be covered with an occlusive dressing such as Tegaderm.

The same tube can be used for a second session as long as the session occurs in 7 days or less and the open tube is kept in a refrigerator.

Patients should stay inside and avoid exposure to sunlight, bright artificial lights, or cold between MAL application and light exposure.

Three hours after application of the MAL cream, the dressing should be removed and the area rinsed with saline. The lesions should be immediately exposed to 37 J/cm2 of red light with the Aktilite source, which corresponds to a time of approximately 9 minutes with a distance of 5-8 cm between the device and the lesion surface. The patient, operator, and any other persons present should wear red-protective goggles during light treatment.

After light treatment, patients should not expose themselves to sunlight or intense light for at least 48 hours. Noncompliance can result in a severe phototoxic reaction.

A second treatment 7 days later is recommended in the FDA-approved protocol.

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