Photodynamic therapy (PDT) relies on the interaction between a photosensitizer, the appropriate wavelength, and oxygen to cause cell death. First introduced about 100 years ago, PDT has continued to evolve in dermatology into a safe and effective treatment option for several dermatologic conditions. PDT is also used by pulmonologists, urologists, and ophthalmologists. This article focuses on the history of PDT, mechanism of action, photosensitizers and light sources used, therapeutic applications and expected dermatologic outcomes, as well as management of adverse events.
Key points
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Over the past 100 years, photodynamic therapy (PDT) has evolved into a safe and effective treatment option for actinic keratosis, superficial nonmelanoma skin cancer (NMSC), and more recently, photoaging, acne, and verrucae.
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PDT is the interaction among 3 ingredients: light, a photosensitizer, and oxygen. This interaction generates reactive oxygen species (ROS), especially singlet oxygen radicals, which cause cell death by necrosis or apoptosis.
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The 2 commonly used photosensitizers, aminolevulinic acid (ALA) and methyl aminolevulinate (MAL), are metabolized by cells into the photoactive porphyrin, protoporphyrin IX (PpIX). Thus, an incubation period is required.
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Red or blue light are commonly used light sources to activate the photosensitizer.
Introduction
PDT relies on the interaction between a photosensitizer, the appropriate wavelength, and oxygen. The reaction generates ROS in cells that take up the photosensitizer, causing cell death by necrosis or apoptosis, but spares the surrounding tissue. Initially, PDT relied on systemic administration of the photosensitizer, but the advent of a topical application revolutionized the field. Over the past 100 years, PDT has evolved into a safe and effective dermatologic treatment option for actinic keratosis/cheilitis, superficial NMSC, and more recently, photoaging, acne, sebaceous hyperplasia, and verrucae. Furthermore, PDT has also expanded outside dermatology, and it is now used as adjuvant therapy to treat pulmonary, respiratory tract, neural, and urinary tract tumors, as well as vitreoretinal disease.
Introduction
PDT relies on the interaction between a photosensitizer, the appropriate wavelength, and oxygen. The reaction generates ROS in cells that take up the photosensitizer, causing cell death by necrosis or apoptosis, but spares the surrounding tissue. Initially, PDT relied on systemic administration of the photosensitizer, but the advent of a topical application revolutionized the field. Over the past 100 years, PDT has evolved into a safe and effective dermatologic treatment option for actinic keratosis/cheilitis, superficial NMSC, and more recently, photoaging, acne, sebaceous hyperplasia, and verrucae. Furthermore, PDT has also expanded outside dermatology, and it is now used as adjuvant therapy to treat pulmonary, respiratory tract, neural, and urinary tract tumors, as well as vitreoretinal disease.
Historical perspective
Ancient civilizations have known for thousands of years that they could combine different plants with sunlight to treat various skin diseases. It was not until about 100 years ago that Hermann von Tappeiner coined the term photodynamic action to describe an oxygen-dependent reaction after photosensitization. He noted that in the absence of oxygen, dye and light alone did not cause cell death. He continued to develop the concept of PDT, and eventually described the first cases in humans, using eosin as the photosensitizer to treat various skin conditions, including condyloma lata and NMSC.
Over the years, many photosensitizers have been used, and the most studied agent is hematoporphyrin. However, hematoporphyrin had to be administered intravenously and was cleared from tissue slowly, resulting in prolonged phototoxicity. It was not until 1990 that Kennedy and colleagues reported the use of 5-ALA and visible light for topical PDT treatment of the skin. ALA was revolutionary, because it easily penetrated damaged or abnormal stratum corneum and rapidly cleared. Using a single application to treat basal cell carcinoma (BCC), Kennedy and colleagues were able to achieve a 90% complete response rate.
Mechanism of action
PDT is the interaction among 3 ingredients: light, a photosensitizer, and oxygen ( Fig. 1 ). After exposure of the photosensitizer to light containing its action spectrum, ROS, especially singlet oxygen radicals, are generated. The ROS affect all intracellular components, including proteins and DNA, resulting in necrosis or apoptosis. Thus, only cells with intracellular photosensitizer are selectively damaged, and the surrounding tissue is spared, resulting in an outstanding cosmetic result.
Sensitizer
The multiple early photosensitizers, including eosin red and the hematoporphyrin derivatives, were not widely used in dermatology because they had an unfavorable side effect profile. The advent of 5-ALA revolutionized PDT. The photosensitizer 5-ALA has a low molecular weight, which allows it to easily penetrate the stratum corneum and be cleared from the skin within 24 to 48 hours of application. ALA is the first compound synthesized in the porphyrin-heme pathway (see Fig. 1 ) and is converted endogenously into the photosensitizer PpIX. Once PpIX is exposed to its action spectra (including 400–410 nm and 635 nm), ROS are generated, which destroy the target cell. Although the heme synthesis pathway is controlled by ALA synthase, exogenous ALA bypasses this rate-limiting enzyme and overwhelms the cell’s ability to convert PpIX into heme. ALA is thought to preferentially target tumors of epithelial origin because of their defective epidermal barrier and slower conversion of PpIX into heme. In the United States, ALA is available as a 20% solution and is marketed under the trade name Levulan.
An alternative to ALA is the methyl ester form, MAL. The presence of methyl ester group makes the molecule more lipophilic and enhances penetration; however, it must be converted back to ALA by intracellular enzymes. Although this may limit the availability of ALA, MAL has been shown to have better tumor selectivity and to reach maximal intracellular concentrations of PpIX quickly, allowing a shorter incubation period. In the United States, MAL was available for a brief period as a 16.8% cream under the trade name Metvixia. However, it is currently unavailable in the US market because of economic reasons, but remains widely used in Europe.
Light source
Several light sources, including coherent and incoherent light, have been used in PDT. PpIX has a strong absorption peak at 405 nm, along with several smaller Q bands; the last peak is at 635 nm. Blue light, which includes the wavelength 405 nm, efficiently excites PpIX and is commonly used. However, because of its relatively short wavelength, it does not penetrate deeply. For thicker lesions, red light, which includes the wavelength 635 nm, is frequently used. This wavelength targets the last Q band; because red light does not excite PpIX as efficiently as blue light, a higher fluence (dose) is needed. Multiple other light sources that take advantage of the action spectrum of PpIX have been used, including intense pulsed light (IPL), pulsed dye laser (585 nm), and natural sunlight.
It is important to consider the fluence (Joules per square centimeter) and irradiance (milliwatts per square centimeter) that are used in PDT. The effective photosensitizing dose for a light source of approximately 405 nm is 10 J/cm 2 , and a 10-fold increase, or 100 J/cm 2 for a light source of 635 nm. Because PDT consumes oxygen, it is important to use an appropriate rate of fluence (ie, irradiance), because a high irradiance may consume the oxygen molecules too quickly, leading to a decrease in efficiency. For this reason, a typical PDT treatment with blue light takes about 15 minutes and a treatment with red light takes about 30 minutes. Red light requires a longer irradiation period because it does not excite PpIX as efficiently as blue light.
Therapeutic applications and expected outcomes
Since the advent of PDT, the list of indications has continued to grow. The following section focuses on the treatment and expected outcomes of photorejuvenation, acne, verrucae, actinic keratosis, and NMSC. The readers are referred to Tables 1 and 2 as well as Box 1 , which outline therapeutic applications and expected outcomes of PDT and a general PDT protocol as well as typical settings used in PDT, respectively.
| Indication | Summary of Recommendations |
|---|---|
| Photorejuvenation | Excellent cosmetic results for all facets of photodamage Multiple other proven and accepted modalities, which are less expensive and require less time |
| Acne vulgaris | Highly effective in the treatment of inflammatory papules, but not comedones Excellent option for moderate to severe acne when isotretinoin is not an option Drawbacks include time commitment, discomfort during treatment, posttreatment erythema, and crusting |
| Verrucae | Very effective Reported clearance rates of hand and foot warts ranging from 56%–100% Reported clearance rates of condyloma accuminata ranging from 66%–79% |
| Actinic keratosis | Highly effective When treating head and neck, efficacy similar to, or exceeds other FDA-approved modalities Better cosmetic outcome when compared with cryotherapy |
| Bowen disease | Efficacy likely superior to cryotherapy and 5-FU Good cosmetic outcome |
| Superficial basal cell carcinoma | Highly effective and similar to simple excisions Useful in treating multiple lesions Main disadvantage is time commitment |
| Nodular basal cell carcinoma | Not recommended at this time |
| Indication | Topical Photosensitizer | Incubation Period | Light Source | Dose | Comments |
|---|---|---|---|---|---|
| Photorejuvenation | ALA | 30 min–3 h | Blue light | 10 J/cm 2 | 2–3 treatments, repeated monthly |
| IPL | 37 J/cm 2 | ||||
| MAL | 30 min–1 h | Red light | 37 J/cm 2 | ||
| Acne vulgaris | ALA | 3 h | Blue light | 10 J/cm 2 | 2–3 treatments, repeated monthly |
| Red light | 37 J/cm 2 | ||||
| MAL | 3 h | Red light | 37 J/cm 2 | ||
| Verrucae | ALA | 4 h | Red light | ≥100 J/cm 2 | 4–5 treatments, repeated biweekly |
| Actinic keratosis | ALA | 4 h | Blue light | 10 J/cm 2 | Requires 1–2 sessions of PDT for optimal results |
| Red light | 75–150 J/cm 2 | ||||
| MAL | 3 h | Red light | 37–75 J/cm 2 | ||
| Bowen disease | ALA | 4 h | Red light | ≥100 J/cm 2 | Requires 2–3 sessions of PDT for optimal results |
| MAL | 3 h | Red light | 75–100 J/cm 2 | ||
| Superficial basal cell carcinoma | ALA | 3–6 h | Red light | ≥60 J/cm 2 | Requires 2–3 sessions of PDT for optimal results |
| MAL | 3 h | Red light | 37–75 J/cm 2 |
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Patient washes the area to be treated with soap and water
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Acetone or Alcohol soaked 4 × 4 gauze is used to remove any remaining debris and oil
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The photosensitizer is evenly applied to the entire area to be treated. A second coat of the photosensitizer can be applied, after the first coat has dried.
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Allow the photosensitizer to incubate for 2–3 hours (see below for more comprehensive recommendations).
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Activate the photosensitizer with the appropriate light source.
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The patient must stay out of the any direct sunlight for 48 hours
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The treatment is repeated as needed in 2–3 weeks
Photorejuvenation
Multiple clinical studies have consistently demonstrated excellent cosmetic results with the use of PDT. Babilas and colleagues, in a prospective, randomized controlled, split-face study, treated with MAL 25 patients with sun-damaged skin followed by irradiation with either a light-emitting diode (635 nm, 37 J/cm 2 ) or an IPL device (610–950 nm, 80 J/cm 2 ). At 3 months, the investigators found significant improvement in wrinkling and pigmentation, irrespective of the light source used. Gold and colleagues evaluated short-contact (30–60 minutes) ALA-PDT using IPL as a light source, versus IPL alone in 16 patients in a side-by-side design. Patients were exposed to PDT for a total of 3 monthly treatments and followed up at months 1 and 3. The IPL treatment parameters were 34 J/cm 2 ; cutoff filters used were 550 nm for Fitzpatrick skin types I to III and 570 nm for Fitzpatrick skin type IV. The investigators found greater improvement in the ALA-PDT-IPL group, compared to patients who received IPL alone for all facets of photodamage.
The practical challenge with using PDT for photorejuvenation is the availability of multiple other proven and accepted modalities such as chemical peels, laser, and IPL. The additional time and supply costs of PDT limit it from becoming a widely used treatment option for photorejuvenation.
Acne Vulgaris
Propionibacterium acnes produce an endogenous porphyrin, coproporphyrin III, which makes it ideal for treatment with PDT. In addition, both ALA and MAL are strongly absorbed by the pilosebaceous unit. Two studies used biopsies to examine the effect of PDT on sebaceous glands. One used a high-dose light source (550–700 nm at 150 J/cm 2 ), and the other used a low-dose light source (600–700 nm at 13 J/cm 2 ). Both regimens caused sebocyte suppression, but suppression by the high-dose light source lasted longer. Furthermore, Wiegell and Wulf compared the efficacy of ALA-PDT to MAL-PDT for the treatment of acne in a randomized, split-face, investigator-blinded study. Patients underwent one treatment and were followed up for 12 weeks. Both photosensitizers were applied for 3 hours under occlusion, followed by irradiation with red light (635 nm, 37 J/cm 2 ). The investigators found an average reduction of 59% in inflammatory lesions, in both the ALA and MAL treatment groups, but no reduction in the number of noninflammatory lesions; there was no statistical difference between the 2 drugs. Finally, in a review of PDT studies for treatment of acne, Sakamoto and colleagues concluded that incubation periods of at least 3 hours were associated with long-term remission, high-dose ALA-PDT and MAL-PDT (with an incubation period of at least 3 hours, high fluence, and red light) have similar efficacy, and red light is more likely to destroy sebaceous glands than blue or pulsed light.
In clinical practice, treatment of acne with PDT is an important modality ( Fig. 2 ). The efficacy of PDT for inflammatory lesions is superior to that of antibiotics in most cases, but inferior to that of isotretinoin. Thus, it is a useful treatment option for patients with moderate to severe inflammatory acne who are poor candidates for isotretinoin. Noninflammatory lesions do not seem to be affected, which can be treated with adjunctive retinoids or physical extraction. Limitations include time commitment, discomfort during treatment, posttreatment erythema, cost, and crusting.
