Photodynamic therapy (PDT) is a rapidly developing, diversely used form of treatment with a variety of applications in dermatology. PDT uses a photosensitizing agent, typically aminolevulinic acid (ALA) or methyl ALA (MAL), which is applied topically to the treatment area. Upon exposure to a light source, the photosensitizer undergoes an oxygen-mediated biochemical reaction resulting in the formation of reactive oxygen intermediates and leads to cellular apoptosis and necrosis (Wan & Lin, 2014). PDT is widely used in dermatology as a primary treatment for premalignant and malignant skin conditions, including actinic keratosis (AK), nonmelanoma skin cancers (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]), and cutaneous T-cell lymphoma (CTCL).
BACKGROUND
PDT was first developed at the beginning of the 20th century and has since been used successfully in various fields of medicine, including dermatology, oncology, and ophthalmology. Treatment methods and research involving PDT have continued to improve over the last century, including landmark indications by the United States Food and Drug Administration for the treatment of AK with ALA-based PDT (ALA-PDT) and MAL-based PDT (MAL-PDT) in 1999 and 2004, respectively. More recent advancements within the last 20 years have caused PDT to gain considerable popularity in dermatology, largely because of an increased understanding of photobiology and skin tissue optics (Garcia-Zuazaga, Cooper, & Baron, 2005). In addition to its widespread applications in dermatology, PDT has been used in the treatment of lung, bladder, gastrointestinal, and gynecological neoplasms (Juarranz, Jaén, Sanz-Rodríguez, Cuevas, & González, 2008). It is also being studied for the treatment of corneal neovascularization, a pathologic condition involving abnormal angiogenesis in the cornea that leads to profound visual impairment (Chang et al., 2012).
MECHANISM OF ACTION
The primary objective of PDT is the selective destruction of abnormal cells with the preservation of normal adjacent structures (Garcia-Zuazaga et al., 2005). This photobiologic response requires a careful combination of the appropriate photosensitizing agent, light energy of a particular wavelength, and molecular oxygen. The photosensitizer absorbs a photon of visible light and then transfers most of this absorbed energy to a molecule of oxygen (Figure 1). The reaction results in the conversion of oxygen in its ground state to a highly excitable singlet state. Light-induced singlet oxygen acts as a relatively strong oxidizing agent in the tissues that have accumulated the sensitizer, resulting in selective cytotoxic damage and the preservation of healthy tissue (Garcia-Zuazaga et al., 2005).
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FIGURE 1: Schematic representation of the mechanism of action of PDT. PDT requires the presence of three basic elements: photosensitizer, light, and molecular oxygen. The photosensitizer is activated by the light source at a specific wavelength. Following the absorption of light, the photosensitizer is transformed from its ground state to a higher energy singlet state. In this highly labile state, the photosensitizer can revert back to the ground state or further transform into a longer-lived, although still unstable, triplet state. In the presence of molecular oxygen, the triplet state of the photosensitizer can then undergo two types of reactions: Type 1 reactions produce free radicals, while Type 2 reactions result in the production of singlet oxygen, which is mainly responsible for the cytotoxic effects of PDT (
Garcia-Zuazaga et al., 2005). Reprinted with permission.
The wavelengths of different light sources have varying depths of penetration into the skin. The effective wavelengths for PDT lie within the visible part of the spectrum, with wavelengths of 470–700 nm. There is a positive correlation between the depth of photon penetration and increased wavelength. Shorter wavelength blue light (417 nm) allows for photosensitizer absorption into most epidermal lesions, whereas longer wavelength red light (630 nm) is more effective for dermal lesions (Garcia-Zuazaga et al., 2005).
PHOTOSENSITIZERS
ALA-based PDT
ALA-PDT utilizes 20% 5-ALA as a prodrug, which is converted into its active form of protoporphyrin IX (PpIX) upon incorporation into the skin (Gold, 2009). The major absorption peak for ALA is seen in the blue light range, between 410 and 420 nm. Several smaller absorption peaks are also seen (Figure 2), leading to the use of a variety of other lasers and light sources known to activate ALA, including potassium-titanyl-phosphate lasers, pulsed dye lasers, and intense pulsed light sources. Red light, at 630 nm, can also be used to activate ALA, although supporting clinical research is limited (Gold, 2009).
FIGURE 2: Protoporphyrin IX absorption spectrum (
Gold, 2009). Reprinted with permission.
ALA Esters: MAL-PDT
The methyl ester of ALA, MAL, is also a prodrug that is converted to PpIX when applied to the skin (Gold, 2009). MAL is more hydrophobic and lipophilic than its parent compound, allowing for increased tissue penetration into targeted skin cells. MAL-PDT is best utilized with a red light source at 630 nm (Gold, 2009). In the United States, MAL was approved by the Food and Drug Administration for the treatment of AKs in 2004. In Europe, it has been approved for AKs and BCC since 2001 (Lee & Baron, 2011).
APPLICATIONS OF PDT IN DERMATOLOGY
Since its initial introduction, the list of PDT applications has grown to include numerous malignant and premalignant conditions as well as various inflammatory disorders and cutaneous infections. In the field of dermatology, PDT has been most widely established as a treatment for AK and nonmelanoma skin cancers, particularly Bowen’s disease (SCC in situ [SCCIS]) and superficial BCC as well as CTCL (Darlenski & Fluhr, 2013). Although research is limited, off-label uses and ongoing investigations continue to increase in the therapeutic management of acne, rosacea, photoaging/antiaging/photorejuvenation, onychomycosis, leishmaniasis, and warts, among others (Lee & Baron, 2011). This article will cover AK, SCC, BCC, and CTCL. Further discussion of common off-label uses for PDT will be addressed in Part 2 of this article series.
ACTINIC KERATOSIS
AK (Figure 3) is the most common precancerous lesion of the skin (Lee & Baron, 2011). Most commonly occurring as a result of chronic ultraviolet exposure, AKs represent a premalignant continuum to the more invasive SCC (Figure 4) (Garcia-Zuazaga et al., 2005). Current evidence suggests that AK is one of the strongest indications for PDT treatment, with cure rates ranging from 69% to 100%. These clearance rates are consistent with those reported for conventional forms of therapy, which include liquid nitrogen cryotherapy, curettage, topical application of 5-fluorouracil (5-FU), and topical imiquimod cream (Lee & Baron, 2011).
FIGURE 3: Actinic keratosis (AK). (A) Common presentation of AKs on the balding scalp. (B) Multiple AKs on the forehead. Classic lesions with adherent scale on an erythematous base.
FIGURE 4: Squamous cell carcinoma. A pink, raised, crusted lesion on the skin of the face.
In 1999, Kurwa, Yong-Gee, and Seet conducted a study comparing ALA-PDT with topical 5-FU for the treatment of AKs. Fourteen patients with multiple AKs on the dorsal surfaces of both hands were treated with ALA-PDT to one hand and topical 5-FU to the other hand. Treatment with 20% topical ALA occluded for 4 hours followed by red light irradiation at a dose of 150 J/cm2, and application of 5% topical 5-FU twice daily for 3 weeks showed similar efficacy, with 70% and 73% reduction in surface area for AKs, respectively (Garcia-Zuazaga et al., 2005).
The results of a 2001 University of California Irvine study conducted by Jeffes et al. (2001) offer further evidence for ALA-PDT in the treatment of AKs. In this investigator-blinded, randomized clinical trial, 36 patients applied 20% ALA solution or control vehicle under occlusion for 14–18 hours, followed by irradiation with blue light at a control dose of 10 J/cm2. ALA-PDT showed 88% complete response for the face and scalp AKs, compared with 6% in the placebo-PDT group (Garcia-Zuazaga et al., 2005). In 2004, a larger, multicenter study by Piacquadio and colleagues showed ALA-PDT to be a safe and effective therapeutic option for AKs, with results indicating over 75% clearance of AKs in 89% of patients at 12-week follow-up (Piacquadio et al., 2004).
Like ALA, MAL has been shown to be effective in the treatment of AKs. In a 2003 multicenter trial done by Parisier, an 86%–89% complete response rate was seen in AK lesions after two treatments of MAL-PDT with red light (Lee & Baron, 2011). In another 2003 study comparing MAL-PDT with cryotherapy, Freeman showed that two sessions of MAL-PDT yielded significantly greater efficacy than cryotherapy in the treatment of AKs (91% vs. 68%; Lee & Baron, 2011).
Clinical evidence clearly indicates that AKs are highly responsive to PDT using topical ALA or MAL. PDT is considered the preferred treatment for widespread lesions because of its capacity for field treatment. It also has the advantage of improved cosmetic outcomes when compared with conventional forms of therapy, making it particularly beneficial for lesions in cosmetically sensitive areas such as the face (Lee & Baron, 2011).
BOWEN’S DISEASE (SCCIS)
Bowen’s disease, or SCCIS, most often appears as a scaly, crusted, erythematous well-demarcated plaque on sun-exposed surfaces such as the scalp, face, and extremities (Figure 5). Malignant invasion into the underlying dermis occurs in 3%–20% of cases, with subsequent metastasis occurring in greater then one third of patients with dermal involvement (Lee & Baron, 2011).
FIGURE 5: Bowen’s lesion (squamous cell carcinoma in situ) on the scalp. Squamous cell carcinoma can have a similar clinical appearance to actinic keratosis.
Surgical excision remains the gold standard for treatment; however, studies have shown promising results for ALA-PDT treatment of SCCIS. Morton et al. (1996) was the first to show that ALA-PDT is as effective as cryotherapy for biopsy-proven SCCIS. Seventy-five percent of Bowen’s lesions were cleared after one treatment of 20% topical ALA under occlusion for 4 hours, followed by irradiation with red light at 125 J/cm2, compared with 50% clearance of lesions treated with liquid nitrogen cryotherapy (Garcia-Zuazaga et al., 2005). Lesion clearance of 100% was seen after two treatment sessions of ALA-PDT, whereas cryotherapy required three sessions to show a complete response. Complications such as ulceration, infection, and disease recurrence were reported in the cryotherapy group only, suggesting that ALA-PDT is an effective treatment modality with the potential for fewer adverse effects (Lee & Baron, 2011).
ALA-PDT has also been shown to be superior to 5-FU in both immediate and long-term efficacies. In a study of 40 patients, Salim, Leman, McColl, Chapman, and Morton (2003) compared the effectiveness of ALA-PDT with topical 5-FU for the treatment of biopsy-proven Bowen’s disease. Patients in the 5-FU group were treated with topical 5-FU once daily for 1 week and then twice daily for 3 weeks. The ALA-PDT group was treated with 20% ALA solution under occlusion for 4 hours, followed by light irradiation at 100 J/cm2 (Garcia-Zuazaga et al., 2005). Initial complete response was seen with 88% of lesions in the ALA-PDT treatment group versus 67% in the topical 5-FU group. Patients treated with 5-FU experienced increased adverse reactions as well as increased recurrence. At 12-month follow-up, higher recurrence rates were seen with 5-FU than with ALA-PDT, with 7% recurrence versus 27%, respectively (Lee & Baron, 2011).
Studies have also shown MAL-PDT as an effective treatment modality for Bowen’s disease. In a large multicenter trial involving 40 European medical centers, Morton et al. observed 86% complete response with MAL-PDT at 3 months, which was comparable with both cryotherapy and 5-FU. At 12 months, 80% sustained response with MAL-PDT was significantly superior to that seen with the other two treatment modalities. Cosmetic outcomes were also improved with MAL-PDT over cryotherapy or 5-FU (Lee & Baron, 2011).
Current guidelines suggest that primary treatment of Bowen’s disease with PDT should be considered in patients with large or multiple lesions and those with patches involving poor healing sites, such as the lower leg. For more invasive tumors and for head and neck lesions, PDT may be used as an adjuvant treatment but is not considered a first-line therapeutic modality (Garcia-Zuazaga et al., 2005).
BASAL CELL CARCINOMA
BCC is the most common skin cancer. Although metastasis of BCC is rare, the lesions have the potential to grow aggressively and cause extensive tissue destruction. BCC most commonly occurs on the head and neck (Figure 6), with a particularly high incidence of development on the nose (25%–30%; Lee & Baron, 2011). The current standard for BCC therapy has been surgery or other forms of ablation. Given the cosmetically sensitive location of lesions, PDT represents an attractive noninvasive treatment alternative. However, PDT alone for the treatment of BCC is controversial because of the various histologic presentations of BCC (superficial, nodular, morpheaform; Lee & Baron, 2011).
FIGURE 6: Basal cell carcinoma. (A) A red, ulcerated lesion on the skin of the right ear with characteristic pearly rim. (B) Lesions can resemble eczema or psoriasis.
ALA-PDT has not been shown to be an effective option for treatment of nodular BCCs. In one randomized control trial (n = 173), recurrence rates for nodular BCC at 3-year follow-up were substantially higher with PDT (30.3%) than with surgical excision (2.3%; Wan & Lin, 2014). With tumor thickness as a significant factor limiting therapeutic response, Morton et al. concluded that ALA-PDT is effective for superficial BCCs less than 2 mm thick and for large or multiple lesions, but not for nodular lesions (Lee & Baron, 2011).
In contrast to ALA-PDT, multiple phase III trials have shown high efficacy and reliability of MAL-PDT in the treatment of nodular BCCs. Greater efficacy of MAL may be attributed to its higher lipophilicity, faster skin penetration, and higher selectivity (Lee & Baron, 2011). In a 2003 study, Horn and colleagues showed 87% clearance in nodular lesions at 3-month follow-up after one-to-two sessions of MAL-PDT. In a similar study conducted by Vinciullo et al. in 2005, nodular BCCs showed a favorable response to MAL-PDT, with a reported clearance rate of 87% at 3-month follow-up. Another multicenter study by Rhodes et al. (2004) found no significant difference in complete response rates for nodular BCC treated with MAL-PDT versus surgery (98% vs. 91%). However, at 24-month follow-up, higher recurrence rate was seen after MAL-PDT than after surgery, with 9.4% recurrence of lesions in the PDT group versus 1.9% after surgery. In a subsequent study comparing recurrence rates at longer 5-year follow-up, the authors again reported a higher trend of recurrence with PDT (14%) than with surgical excision (4%; Lee & Baron, 2011).
Although surgery remains as the first-line therapy for BCC, the cosmetic advantages of PDT are of interest for low-risk superficial BCCs, particularly for multiple lesions and those affecting skin sites predisposed to dystrophic scarring. PDT is also being studied in the treatment of nevoid BCC syndrome (Gorlin–Goltz syndrome). Gorlin–Goltz syndrome is a rare hereditary condition caused by a mutation in the PTCH1 gene located on chromosome 9q22.3-q31 (Larsen, Mickelson, Hertz, & Bygum, 2014). Among other developmental abnormalities, these patients experience multiple BCCs, often requiring extensive surgical interventions and significant scarring. In 2005, Oseroff and colleagues reported the successful use of wide-area ALA-PDT in three patients with Gorlin–Goltz syndrome. The authors described overall clearance rates between 85% and 98% with excellent cosmetic results (Garcia-Zuazaga et al., 2005). ALA-PDT may represent the most practical treatment modality for this subset of patients, and research regarding a standardized treatment protocol for this condition is ongoing.
CUTANEOUS T-CELL LYMPHOMA
CTCL refers to a diverse group of neoplasms composed of T-lymphocytes localized to the skin. Mycosis fungoides (MF) is the most common, indolent subtype of CTCL, accounting for approximately 70% of cases (Lee & Baron, 2011). Clinically, patients with MF progress from patch to plaque to tumor stages. In early patch-stage MF, standard treatments include topical corticosteroids, cytotoxic agents, phototherapy, and radiotherapy. In more advanced disease, systemic chemotherapy and immunomodulatory therapies such as interferon and bexarotene may be used (Garcia-Zuazaga et al., 2005).
PDT has been widely used in the treatment of MF. Despite limited investigations because of the rarity of this disease, a few studies and various case reports have reported complete or partial response in MF lesions after treatment with PDT. Most studies to date report efficacy of MAL-PDT and ALA-PDT in the treatment of plaque-type (Stage 1) MF but decreased efficacy against tumor-type (Stage 2) MF (Wan & Lin, 2014). In 2004, Coors and von den Driesch reported complete remission of MF lesions at 3-month follow-up in four patients treated with ALA-PDT (Garcia-Zuazaga et al., 2005). A 2013 prospective study by Quereux et al. reported an objective response in 75% of plaque or patchy lesions after monthly treatments for 6 months, although two of five patients who appeared to have complete responses initially were reported to have relapsed at follow-up (Wan & Lin, 2014). MAL-PDT has been successfully used in cases of treatment refractory MF, with four patients showing complete remission and one with partial remission after therapy. On the basis of these preliminary findings, several consecutive treatments of PDT can be considered as appropriate adjunctive treatment for MF, particularly for patch- and plaque-stage disease, with good cosmetic results in sensitive skin areas (Wan & Lin, 2014).
FUTURE DIRECTIONS
PDT has become an important component of skin cancer therapy. It is based on photobiologic mechanisms that can be tailored according to the characteristics of the photosensitizer and the target lesions. Future research is emerging regarding the use of novel photosensitizers, and the field of PDT will continue to expand as new photosensitizers emerge in the market. Combination therapy is also expected to become the new standard of care for PDT in patients with skin cancer (Wan & Lin, 2014). Preliminary studies have shown favorable results with combination PDT and topical imiquimod as well as temperature-modulated PDT, particularly for the treatment of AK on the extremities. In a report of three cases, Held, Eigentler, Leiter, Garbe, and Berneburg showed that the sequential application of PDT and 5% imiquimod cream was a well-tolerated, safe, and highly efficacious treatment method for AK with excellent cosmetic results (Held et al., 2013).
In addition, there is a strong relationship between temperature and porphyrin synthesis in biologic tissue, and the conversion of ALA to its active metabolite, PpIX, can be modulated by temperature (Willey, Anderson, & Sakamoto, 2014). On the basis of this premise, Willey and colleagues conducted a pilot study to investigate the effects of increasing the temperature of the skin during the incubation of ALA. The primary aim of this study was to evaluate the efficacy and tolerability of temperature-modulated PDT for the treatment of AKs on the distal extremities, for which the efficacy of current PDT protocols is greatly reduced (Willey et al., 2014). The authors found that moderately increasing the skin temperature during the incubation of ALA enhanced the PDT reaction in the skin. After a single treatment, results indicated increased efficacy of AK clearance on the distal extremities to a level comparable with published data for AKs on the face and scalp. Warming the skin was generally well tolerated, although there were reports of increased stinging during light exposure and increased PDT skin reactions after treatment (Willey et al., 2014). To date, neither form of combination therapy (imiquimod or temperature modulation) has been widely studied in the literature, and ongoing investigations and larger scale trials are expected to be forthcoming.
CONCLUSIONS
PDT has been well established for the treatment of AK and superficial nonmelanoma skin cancers and is gaining attention for various other nononcological cutaneous conditions. PDT has been associated with faster recovery periods and superior cosmetic results when compared with other conventional treatments. As a noninvasive treatment option capable of field therapy, PDT can be considered a preferred modality for poor surgical candidates or those with multiple or cosmetically sensitive lesions (Lee & Baron, 2011). PDT is expected to continue to grow and expand in its utilization, with future developments focused on additional indications as well as improvements in vehicles and delivery systems. Further advancements in treatment protocols are targeted toward increasing efficacy while reducing the side effect profile and allowing for optimal cosmetic outcomes (Wan & Lin, 2014).
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