Current Evidence and Applications of Photodynamic Therapy in Dermatology Part 1: Cutaneous Neoplasms

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FEATURE ARTICLE 2.5 Contact Hours Current Evidence and Applications of Photodynamic Therapy in Dermatology Part 1: Cutaneous Neoplasms

Jaclyn S. Effron, Hannah Aliazzi, Jorge Garcia-Zuazaga

ABSTRACT: Photodynamic therapy (PDT) involves the hotodynamic therapy (PDT) is a rapidly dev- activation of a topical photosensitizing drug with expo- eloping, diversely used form of treatment with sure to a light source. Commonly used agents in PDT a variety of applications in dermatology. PDT include 5-aminolevulinic acid and methyl aminolevulinic uses a photosensitizing agent, typically amino- acid. These medications preferentially localize to dis- levulinic acid (ALA) or methyl ALA (MAL), eased skin, resulting in selective cytotoxic damage and which is applied topically to the treatment area. Upon immunomodulation. In addition to the advantages of Pexposure to a light source, the photosensitizer undergoes PDT as being noninvasive and capable of field treatment, an oxygen-mediated biochemical reaction resulting in the PDT has also been associated with reduced recovery formation of reactive oxygen intermediates and leads to time and improved cosmetic results. This article is Part 1 cellular apoptosis and necrosis (Wan & Lin, 2014). PDT of a two-part series reviewing the state of current evi- is widely used in dermatology as a primary treatment for dence and applications of PDT in dermatology. Part 1 premalignant and malignant skin conditions, including will address PDT as treatment for cutaneous neoplasms, actinic keratosis (AK), nonmelanoma skin cancers (basal namely, actinic keratosis and nonmelanoma skin can- cell carcinoma [BCC] and squamous cell carcinoma [SCC]), cers. Part 2 will follow with a discussion of more recent and cutaneous T-cell lymphoma (CTCL). indications for PDT in dermatology, such as acne and photorejuvenation. Key words: Actinic Keratosis (AK), Basal Cell Carcinoma BACKGROUND (BCC), Bowen’s Disease, Cutaneous T-Cell Lymphoma (CTCL), Photodynamic Therapy (PDT), Squamous Cell PDT was first developed at the beginning of the 20th Carcinoma (SCC) 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, Jaclyn S. Effron, CNP, Apex Dermatology and Skin Surgery Center, Concord, OH. including landmark indications by the United States Food Hannah Aliazzi, Apex Dermatology and Skin Surgery Center, and Drug Administration for the treatment of AK with Concord, OH. ALA-based PDT (ALA-PDT) and MAL-based PDT Jorge Garcia-Zuazaga, MD, FAAD, Apex Dermatology and Skin (MAL-PDT) in 1999 and 2004, respectively. More recent Surgery Center, Concord, OH. advancements within the last 20 years have caused PDT to The authors and planners have disclosed that they have no financial gain considerable popularity in dermatology, largely be- relationships related to this article. cause of an increased understanding of photobiology and Correspondence concerning this article should be addressed to Jaclyn S. Effron, CNP, Apex Dermatology and Skin Surgery Center, skin tissue optics (Garcia-Zuazaga, Cooper, & Baron, 7580 Auburn Road, Suite 301 Concord, OH 44077. 2005). In addition to its widespread applications in der- E-mail: [email protected] matology, PDT has been used in the treatment of lung, DOI: 10.1097/JDN.0000000000000128 bladder, gastrointestinal, and gynecological neoplasms

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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.

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Copyright © 2015 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. FIGURE 2. Protoporphyrin IX absorption spectrum (Gold, 2009). Reprinted with permission. and cutaneous infections. In the field of dermatology, PDT In 1999, Kurwa, Yong-Gee, and Seet conducted a study has been most widely established as a treatment for AK comparing ALA-PDT with topical 5-FU for the treatment and nonmelanoma skin cancers, particularly Bowen’s dis- of AKs. Fourteen patients with multiple AKs on the ease (SCC in situ [SCCIS]) and superficial BCC as well as dorsal surfaces of both hands were treated with ALA-PDT CTCL (Darlenski & Fluhr, 2013). Although research is to one hand and topical 5-FU to the other hand. Treat- limited, off-label uses and ongoing investigations continue ment with 20% topical ALA occluded for 4 hours fol- to increase in the therapeutic management of acne, rosacea, lowed by red light irradiation at a dose of 150 J/cm2,and photoaging/antiaging/photorejuvenation, onychomycosis, application of 5% topical 5-FU twice daily for 3 weeks leishmaniasis, and warts, among others (Lee & Baron, 2011). showed similar efficacy, with 70% and 73% reduction in This article will cover AK, SCC, BCC, and CTCL. Further surface area for AKs, respectively (Garcia-Zuazaga et al., discussion of common off-label uses for PDT will be 2005). addressed in Part 2 of this article series. The results of a 2001 University of California Irvine study conducted by Jeffes et al. (2001) offer further evi- ACTINIC KERATOSIS dence for ALA-PDT in the treatment of AKs. In this AK (Figure 3) is the most common precancerous lesion of investigator-blinded, randomized clinical trial, 36 patients the skin (Lee & Baron, 2011). Most commonly occurring applied 20% ALA solution or control vehicle under occlu- as a result of chronic ultraviolet exposure, AKs represent a sion for 14Y18 hours, followed by irradiation with blue premalignant continuum to the more invasive SCC (Figure 4) light at a control dose of 10 J/cm2.ALA-PDTshowed88% (Garcia-Zuazaga et al., 2005). Current evidence suggests complete response for the face and scalp AKs, compared that AK is one of the strongest indications for PDT treat- with 6% in the placebo-PDT group (Garcia-Zuazaga et al., ment, with cure rates ranging from 69% to 100%. These 2005). In 2004, a larger, multicenter study by Piacquadio clearance rates are consistent with those reported for con- and colleagues showed ALA-PDT to be a safe and effective ventional forms of therapy, which include liquid nitrogen therapeutic option for AKs, with results indicating over 75% cryotherapy, curettage, topical application of 5-fluorouracil clearance of AKs in 89% of patients at 12-week follow-up (5-FU), and topical imiquimod cream (Lee & Baron, 2011). (Piacquadio et al., 2004).

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Copyright © 2015 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. 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. Like ALA, MAL has been shown to be effective in the considered the preferred treatment for widespread lesions treatment of AKs. In a 2003 multicenter trial done by Parisier, because of its capacity for field treatment. It also has the an 86%Y89% complete response rate was seen in AK lesions advantage of improved cosmetic outcomes when compared after two treatments of MAL-PDT with red light (Lee & with conventional forms of therapy, making it particularly Baron, 2011). In another 2003 study comparing MAL-PDT beneficial for lesions in cosmetically sensitive areas such as with cryotherapy, Freeman showed that two sessions of the face (Lee & Baron, 2011). MAL-PDT yielded significantly greater efficacy than cryotherapy in the treatment of AKs (91% vs. 68%; Lee & Baron, 2011). BOWEN’S DISEASE (SCCIS) Clinical evidence clearly indicates that AKs are highly Bowen’s disease, or SCCIS, most often appears as a scaly, responsive to PDT using topical ALA or MAL. PDT is 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%Y20% of cases, with subsequent metastasis occurring in greater then one third of patients with dermal involvement (Lee & Baron, 2011). 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

FIGURE 5. Bowen’s lesion (squamous cell carcinoma in situ) FIGURE 4. Squamous cell carcinoma. A pink, raised, crusted on the scalp. Squamous cell carcinoma can have a similar lesion on the skin of the face. clinical appearance to actinic keratosis.

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Copyright © 2015 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. lesions were cleared after one treatment of 20% topical native. However, PDT alone for the treatment of BCC is con- ALA under occlusion for 4 hours, followed by irradiation troversial because of the various histologic presentations of with red light at 125 J/cm2, compared with 50% clear- BCC (superficial, nodular, morpheaform; Lee & Baron, 2011). ance of lesions treated with liquid nitrogen cryotherapy ALA-PDT has not been shown to be an effective option (Garcia-Zuazaga et al., 2005). Lesion clearance of 100% for treatment of nodular BCCs. In one randomized con- was seen after two treatment sessions of ALA-PDT, whereas trol trial (n = 173), recurrence rates for nodular BCC at cryotherapy required three sessions to show a complete 3-year follow-up were substantially higher with PDT response. Complications such as ulceration, infection, and (30.3%) than with surgical excision (2.3%; Wan & Lin, disease recurrence were reported in the cryotherapy group 2014). With tumor thickness as a significant factor lim- only, suggesting that ALA-PDT is an effective treatment iting therapeutic response, Morton et al. concluded that modality with the potential for fewer adverse effects (Lee & ALA-PDT is effective for superficial BCCs less than 2 mm Baron, 2011). thick and for large or multiple lesions, but not for nodular ALA-PDT has also been shown to be superior to 5-FU lesions (Lee & Baron, 2011). in both immediate and long-term efficacies. In a study of In contrast to ALA-PDT, multiple phase III trials have 40 patients, Salim, Leman, McColl, Chapman, and Morton shown high efficacy and reliability of MAL-PDT in the (2003) compared the effectiveness of ALA-PDT with topical treatment of nodular BCCs. Greater efficacy of MAL may 5-FU for the treatment of biopsy-proven Bowen’s disease. be attributed to its higher lipophilicity, faster skin penetration, Patients in the 5-FU group were treated with topical 5-FU and higher selectivity (Lee & Baron, 2011). In a 2003 once daily for 1 week and then twice daily for 3 weeks. study, Horn and colleagues showed 87% clearance in nod- The ALA-PDT group was treated with 20% ALA solution ular lesions at 3-month follow-up after one-to-two sessions under occlusion for 4 hours, followed by light irradiation of MAL-PDT. In a similar study conducted by Vinciullo et al. at 100 J/cm2 (Garcia-Zuazaga et al., 2005). Initial complete in 2005, nodular BCCs showed a favorable response to response was seen with 88% of lesions in the ALA-PDT MAL-PDT, with a reported clearance rate of 87% at 3-month treatment group versus 67% in the topical 5-FU group. follow-up. Another multicenter study by Rhodes et al. (2004) Patients treated with 5-FU experienced increased adverse found no significant difference in complete response rates reactions as well as increased recurrence. At 12-month for nodular BCC treated with MAL-PDT versus surgery follow-up, higher recurrence rates were seen with 5-FU than (98% vs. 91%). However, at 24-month follow-up, higher with ALA-PDT, with 7% recurrence versus 27%, respectively recurrence rate was seen after MAL-PDT than after surgery, (Lee & Baron, 2011). with 9.4% recurrence of lesions in the PDT group versus Studies have also shown MAL-PDT as an effective treat- 1.9% after surgery. In a subsequent study comparing re- ment modality for Bowen’s disease. In a large multicenter trial currence rates at longer 5-year follow-up, the authors again involving 40 European medical centers, Morton et al. ob- reported a higher trend of recurrence with PDT (14%) than served 86% complete response with MAL-PDT at 3 months, with surgical excision (4%; Lee & Baron, 2011). which was comparable with both cryotherapy and 5-FU. At Although surgery remains as the first-line therapy for 12 months, 80% sustained response with MAL-PDT was BCC, the cosmetic advantages of PDT are of interest for significantly superior to that seen with the other two treat- low-risk superficial BCCs, particularly for multiple lesions ment modalities. Cosmetic outcomes were also improved and those affecting skin sites predisposed to dystrophic scar- with MAL-PDTover cryotherapy or 5-FU (Lee & Baron, 2011). ring. PDT is also being studied in the treatment of nevoid Current guidelines suggest that primary treatment of BCC syndrome (GorlinYGoltz syndrome). GorlinYGoltz syn- Bowen’s disease with PDT should be considered in pa- drome is a rare hereditary condition caused by a mutation in tients with large or multiple lesions and those with patches the PTCH1 gene located on chromosome 9q22.3-q31 (Larsen, involving poor healing sites, such as the lower leg. For more Mickelson, Hertz, & Bygum, 2014). Among other devel- invasive tumors and for head and neck lesions, PDT may be opmental abnormalities, these patients experience multiple used as an adjuvant treatment but is not considered a first-line BCCs, often requiring extensive surgical interventions and therapeutic modality (Garcia-Zuazaga et al., 2005). significant scarring. In 2005, Oseroff and colleagues reported the successful use of wide-area ALA-PDT in three patients BASAL CELL CARCINOMA with GorlinYGoltz syndrome. The authors described overall BCC is the most common skin cancer. Although metas- clearance rates between 85% and 98% with excellent cos- tasis of BCC is rare, the lesions have the potential to grow metic results (Garcia-Zuazaga et al., 2005). ALA-PDT may aggressively and cause extensive tissue destruction. BCC represent the most practical treatment modality for this subset most commonly occurs on the head and neck (Figure 6), of patients, and research regarding a standardized treatment with a particularly high incidence of development on the protocol for this condition is ongoing. nose (25%Y30%; Lee & Baron, 2011). The current standard for BCC therapy has been surgery or other forms of CUTANEOUS T-CELL LYMPHOMA ablation. Given the cosmetically sensitive location of lesions, CTCL refers to a diverse group of neoplasms composed of PDT represents an attractive noninvasive treatment alter- T-lymphocytes localized to the skin. Mycosis fungoides (MF)

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Copyright © 2015 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. 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. is the most common, indolent subtype of CTCL, accounting tizers emerge in the market. Combination therapy is also for approximately 70% of cases (Lee & Baron, 2011). Clin- expected to become the new standard of care for PDT in ically, patients with MF progress from patch to plaque to patients with skin cancer (Wan & Lin, 2014). Preliminary tumor stages. In early patch-stage MF, standard treatments studies have shown favorable results with combination include topical corticosteroids, cytotoxic agents, phototherapy, PDT and topical imiquimod as well as temperature- and radiotherapy. In more advanced disease, systemic chemo- modulated PDT, particularly for the treatment of AK on therapy and immunomodulatory therapies such as interferon the extremities. In a report of three cases, Held, Eigentler, and bexarotene may be used (Garcia-Zuazaga et al., 2005). Leiter, Garbe, and Berneburg showed that the sequential PDT has been widely used in the treatment of MF. application of PDT and 5% imiquimod cream was a well- Despite limited investigations because of the rarity of this tolerated, safe, and highly efficacious treatment method disease, a few studies and various case reports have re- for AK with excellent cosmetic results (Held et al., 2013). ported complete or partial response in MF lesions after In addition, there is a strong relationship between tem- treatment with PDT. Most studies to date report efficacy perature and porphyrin synthesis in biologic tissue, and the of MAL-PDT and ALA-PDT in the treatment of plaque- conversion of ALA to its active metabolite, PpIX, can be type (Stage 1) MF but decreased efficacy against tumor- modulated by temperature (Willey, Anderson, & Sakamoto, type (Stage 2) MF (Wan & Lin, 2014). In 2004, Coors 2014). On the basis of this premise, Willey and colleagues and von den Driesch reported complete remission of MF conducted a pilot study to investigate the effects of increasing lesions at 3-month follow-up in four patients treated with the temperature of the skin during the incubation of ALA. ALA-PDT (Garcia-Zuazaga et al., 2005). A 2013 prospec- The primary aim of this study was to evaluate the efficacy tive study by Quereux et al. reported an objective response and tolerability of temperature-modulated PDT for the treat- in 75% of plaque or patchy lesions after monthly treatment of AKs on the distal extremities, for which the efficacy ments for 6 months, although two of five patients who ap- of current PDT protocols is greatly reduced (Willey et al., peared to have complete responses initially were reported 2014). The authors found that moderately increasing the to have relapsed at follow-up (Wan & Lin, 2014). MAL-PDT skin temperature during the incubation of ALA enhanced has been successfully used in cases of treatment refractory the PDT reaction in the skin. After a single treatment, results MF, with four patients showing complete remission and one indicated increased efficacy of AK clearance on the distal with partial remission after therapy. On the basis of these extremities to a level comparable with published data for preliminary findings, several consecutive treatments of PDT AKs on the face and scalp. Warming the skin was generally can be considered as appropriate adjunctive treatment for MF, well tolerated, although there were reports of increased sting- particularly for patch- and plaque-stage disease, with good ing during light exposure and increased PDT skin reactions cosmetic results in sensitive skin areas (Wan & Lin, 2014). after treatment (Willey et al., 2014). To date, neither form of combination therapy (imiquimod or temperature mod- FUTURE DIRECTIONS ulation) has been widely studied in the literature, and ongoing investigations and larger scale trials are expected to PDT has become an important component of skin cancer be forthcoming. 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 emerg- CONCLUSIONS ing regarding the use of novel photosensitizers, and the PDT has been well established for the treatment of AK field of PDT will continue to expand as new photosensi- and superficial nonmelanoma skin cancers and is gaining

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Copyright © 2015 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited. attention for various other nononcological cutaneous con- topical aminolevulinic acid hydrochloride and fluorescent blue light. Journal of the American Academy of Dermatology, 45(1), 96Y104. ditions. PDT has been associated with faster recovery peri- Juarranz, A., Jae´n, P., Sanz-Rodrmethyl aminolevulinate for actinic keratosis: Results of a prospective randomized multicenter trial. (2012). Corneal neovascularization: An anti-VEGF therapy review. Survey Y of Ophthalmology, 57(5), 415Y429. Journal of American Academy of Dermatology, 48, 227 232. Piacquadio, D. J., Chen, D. M., Farber, H. F., Fowler, J. F. Jr., Glazer, S. D., Coors, E. A., & von den Driesch, P. (2004). Topical photodynamic therapy I for patients with therapy-resistant lesions of cutaneous T-cell lymphoma. Goodman, J. J., Weinstein, G. D. (2004). Photodynamic therapy with Journal of American Academy of Dermatology, 50(3), 363Y367. aminolevulinic acid topical solution and visible blue light in the treatment of multiple AK of the face and scalp: Investigator-blinded, phase 3, multi- Darlenski, R., & Fluhr, J. W. (2013). Photodynamic therapy in dermatology: center trials. Archives of Dermatology, 140(1), 41Y46. Past, present, and future. Journal of Biomedical Optics, 18(6), 061208. Quereux, G., Brocard, A., Saint-Jean, M., Peuvrel, L., Knol, A.-C., Allix, R., I Freeman, M. (2003). A comparison of photodynamic therapy using topical Dre´no, B. (2013). Photodynamic therapy with methyl-aminolevulinic acid methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients for paucilesionlal mycosis fungoides: A prospective open study and review with actinic keratosis: A prospective randomized study. Journal of Derma- of the literature. Journal of American Academy of Dermatology, 69(6), 890Y897. tological Treatment, 14,99Y106. Rhodes, L. E., de Rie, M., Entrom, Y., Groves, R., Morken, T., Goulden, V., Garcia-Zuazaga, J., Cooper, K. D., & Baron, E. D. (2005). Photodynamic I Wolf, P. (2004). Photodynamic therapy using topical aminolevulinate vs therapy in dermatology: Current concepts in the treatment of skin cancer. surgery for nodular basal cell carcinoma: Results of a multicenter ran- Expert Review of Anticancer Therapy, 5(5), 791Y800. domized prospective trial. Archives of Dermatology, 140(1), 17Y23. Gold, M. H. (2009). Therapeutic and aesthetic uses of photodynamic therapy. Salim, A., Leman, J. A., McColl, J. H., Chapman, R., & Morton, C. A. (2003). The Journal of Clinical and Aesthetic Dermatology, 2(2), 44Y47. Randomized comparison of photodynamic therapy with topical 5-fluorouracil Held, L., Eigentler, T. K., Leiter, U., Garbe, C., & Berneburg, M. J. (2013). in Bowen’s disease. British Journal of Dermatology, 148(3), 539Y543. Effective combination of photodynamic therapy and imiquimod 5% Vinciullo, C., Elliott, T., Francis, D., Gebauer, K., Spelman, L., Nguyen R., I cream in the treatment of actinic keratoses: Three cases. Biomed Research Murrell, D. (2005). Photodynamic therapy with topical methyl aminolevulinate International, 2013, 102698. for ‘‘difficult-to-treat’’ basal cell carcinoma. British Journal of Dermatology, Horn, M., Wolf, P., Wulf, H. C., Warloe, T., Fritsch, C., Rhodes, L. E., I 152, 765Y772. Larko¨ , O. (2003). Topical methyl aminolevulinate photodynamic therapy Wan, M. T., & Lin, J. Y. (2014). Current evidence and applications of in patients with basal cell carcinoma prone to complications and poor cosmetic photodynamic therapy in dermatology. Clinical, Cosmetic and Investi- outcome with conventional treatment. British Journal of Dermatology, gational Dermatology, 7,145Y163. Y 149(6), 1242 1249. Willey, A., Anderson, R. R., & Sakamoto, F. H. (2014). Temperature- Jeffes, E. W., McCollough, J. L., Weinstein, G. D., Kaplan, R., Glazer, S. D., modulated photodynamic therapy for the treatment of actinic keratosis on & Taylor, J. R. (2001). Photodynamic therapy of actinic keratosis with the extremities: A pilot study. Dermatologic Surgery, 40(10), 1094Y1102.

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