Review Article

Photodynamic therapy in dermatology

Chitra S. Nayak Department of Dermatology, BYL Nair Hospital and TN Medial College, Mumbai, India

Address for correspondence: Chitra S. Nayak, 302, Arun, 6th Road, Santacruz East, Mumbai - 400055, India. E-mail: [email protected]

ABSTRACT

Photodynamic therapy is a new modality of therapy being used for the diagnosis and treatment of many tumors. It is now being increasingly used for skin tumors and other dermatological disorders. With its range of application it is certainly the therapy of the future. Its mechanism of action is by the Type II photo-oxidative reaction. The variables are the photosensitizer, the tissue oxygenation and the light source. It has been used to treat various disorders including Bowen’s disease, actinic keratoses, squamous cell carcinomas, basal cell carcinomas, and mycosis fungoides. The side-effects are fortunately mild and transient. Newer photosensitisers like methyl aminolevulinate hold a lot of promise for better therapy.

Key Words: Photosensitizer, Light source, Aminolevulinate

HISTORY in the target cells followed by selective irradiation of the lesion with visible light. The drug and light are The use of sunlight for the treatment of various skin individually non-toxic, but in combination destroy disorders (heliotherapy) was known to ancient Indians tissues. and Greeks. In the modern era, Oscar Raab, a German medical student first reported the death of Paramecium MECHANISM OF ACTION caudatum (a protozoan) after light exposure in the presence of acridine orange in the year 1900.[1] His The efficacy of PDT depends on all the following professor, von Tappeiner, coined the term mechanisms which are inter-linked: direct cytotoxicity, “photodynamic” to describe oxygen-consuming vascular damage, inflammation and immune host chemical reactions in vivo. Von Tappeiner and Jesionek response.[2] (a dermatologist), in 1904, used topical eosin and visible light to treat skin tumors, condyloma lata and lupus Direct cytotoxicity: In PDT absorption of a light photon vulgaris.[1] by the sensitizer causes its promotion from the ground state to the extremely unstable short lived excited DEFINITION singlet state. The singlet excited photosensitizer emits fluorescence and decays back to the ground state or to Photodynamic therapy (PDT) is a treatment modality the longer lived triplet excited state. Interaction of the involving administration of a photosensitizing triplet sensitizer with surrounding molecules results compound, accumulation of the sensitizer molecules in photo-oxidative reactions (POR) that release singlet

How to cite this article: Nayak CS. Photodynamic therapy in dermatology. Indian J Dermatol Venereol Leprol 2005;71:155-60. Received: July, 2004. Accepted: November, 2004. Source of Support: Nil. Conflict of interest: None declared.

155 Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 Nayak CS: Photodynamic therapy in dermatology oxygen resulting in phototoxicity. Lipid peroxidation specific immune cells that appear to be directed against leads to cell membrane defects, which result in cell both strongly and poorly immunogenic cancer types. lysis [Figure 1]. Damage to mitochondria, lysosomes or endoplasmic reticulum occurs depending on the Host immune response: Thus mobilization of the host location of the photosensitizer in the cell. As most to participate in the tumor ablation process is a unique photosensitisers do not localize in the nucleus, nuclear feature of PDT and is an advantage over conventional damage is not an important factor of PDT-mediated anticancer therapy. Use of monoclonal antibody- cytotoxicity. sensitizer conjugates results in greater selectivity and higher complete response rates, enhancing the anti- Vascular injury: Vascular injury is important in tumor tumor properties of PDT. destruction mediated by PDT. Vascular endothelial damage leads to platelet and polymorphonuclear Factors affecting efficacy of PDT leucocyte activation that releases pro-aggregatory The variables in PDT are: agents. These events result in arteriolar constriction, 1. Photosensitizer venular thrombosis and blood flow stasis causing 2. Tissue oxygenation indirect tumor cell kill from nutritional deprivation. 3. Light source

Inflammatory response: Degradation of phospholipids Photosensitisers occurring after photo-oxidative damage of cell Photosensitisers that are under various stages of membrane and impairment of vascular functions results investigation for photodynamic therapy are listed in in the release of various inflammatory mediators. This Table 1. An ideal photosensitizer should be chemically leads to accumulation of immune effector cells like pure, have capability of localizing specifically in macrophages and neutrophil granulocytes. neoplastic tissue, should accumulate maximally in Degranulation of neutrophils and release of toxic tumor in short time, and have a short half-life and rapid oxygen radicals, lysosomal enzymes and chemotactic clearance from normal tissues. It should activate at agents contribute to the destruction of the tumor tissue wavelengths with optimal tissue penetration, have a and sustain the damage by attracting further immune high quantum yield for singlet oxygen generation, cells. Establishment of immunological response against should lack dark toxicity and should be effective on the treated malignancy leads to generation of tumor- topical application for dermatological uses.

Systemic PDT Initially, after systemic administration, photosensitizing Photon compounds are taken up by most normal and malignant Excited cells, but are retained longer in tumor and rapidly Photosensitiserizer Singlet State proliferating cells. This may be due to increased blood vessel number and permeability and poor lymphatic Type II POR drainage in neoplastic tissue. In fact, many normal

Singlet O2 tissues, especially the reticuloendothelial system have greater affinity for photosensitisers than tumor tissue. • Lipid peroxidation • Mitochondrial damage Excited Triplet State • Damage to lysosomes The drug is activated by light corresponding to the • Damage to ER absorption spectrum of the compound. The depth of • DNA damage tissue penetration depends on the wavelength of this absorption spectrum. Light of 630 nm wavelength penetrates 5 mm into tissues while that between 700- 800 nm penetrates to 1-2 cm depth. Light at 850 nm Figure 1: Mechanism of photodynamic therapy within cell does not yield enough energy to produce sufficient

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Table 1: Photosensitizers being clinically investigated for PDT Photosensitizer Wavelength for PDT, nm Indications Route of administration Porfimer sodium (Photofrin) 630 Approved for bladder, esophagus, IV lung cancer. Studies for BCC Tin ethyl etiopurpurin (Purlytin) 660-665 Cutaneous metastases, Kaposi’s IV, lipid emulsion sarcoma, macular degeneration 5-aminolevulinic acid (ALA, Levulan) 635 Actinic keratoses, BCC, CTCL, Topical psoriasis, permanent hair removal Lutetium texaphyrin (Lu- Tex) 720-760 Skin cancer IV ATMPn 640 Psoriasis Topical BPD-MA (Verteporfin) 690 BCC, psoriasis, macular degeneration IV, liposomal formulation m-THPC (Foscan) 650 BCC, head and neck cancer IV, topical Npe6 660-665 Skin cancer IV Talaporfin sodium 640 Carcinoma aerodigestive tract IV photochemical response. is an unstable hydrophilic molecule, has poor penetration depth and consequent requirement of long Hematoporphyrin derivative (HpD) was the first application times, has low tissue selectivity and may systemically studied photosensitizer for clinical PDT. cause porphyrin to accumulate in distant sites Photofrin (porfimer sodium) has enhanced photosensitizing properties and consists of non- Methyl aminolevulinate cream is currently being metallic oligomeric porphyrins viz. a mixture of ethers investigated clinically. Its advantages are that it is a and esters of porphyrin.[1] This is activated at 630 nm. stable lipophilic molecule, has greater and faster At this wavelength there is no penetration beyond 5 penetration as well as a greater selectivity for neoplastic mm, hence lesions may not be effectively treated. The cells and shows no systemic uptake. main disadvantage is cutaneous accumulation and slow clearance from skin leading to long lasting cutaneous Tissue oxygenation photosensitivity, as long as 4-6 weeks. Experimental attempts at improving PDT effectiveness by manipulating tumor oxygen content like subjecting Systemic ALA is used to treat gastrointestinal, the tissue to hyperbaric oxygen have been made. bronchopulmonary and cerebral tumors. ALA-based However, this has no place as yet in clinical PDT. PDT can be potentiated with the use of additive compounds to inhibit or induce certain enzymes of the Light sources heme synthesis pathway.[2] The therapeutic window for PDT is between 600 nm 1. Desferrioxamine enhances ALA-induced and 1200 nm as light of wavelength below 600 nm is protoporphyrin IX (PpIX) accumulation. absorbed by hemoglobin in the tissues and that above 2. Combination of DMSO and EDTA with ALA increased 1200 nm is absorbed by water. Light sources may be PpIX production and enhanced the complete coherent (lasers) or incoherent. Laser beams can be response rate of nodular basal cell carcinomas. launched via fiberoptic cables and delivered into internal tumors via implanted fibers. Topical PDT Topical PDT depends on protoporphyrin IX (PpIX) When porphyrin photosensitisers are used, lasers of formed endogenously in tissue after application of d- wavelength around 630 nm are required to match their aminolevulinic acid (d-ALA). Topical application of d- absorption maxima. Argon pumped dye lasers (630 nm) ALA subverts the negative feedback effect on the heme or gold vapor laser (628 nm) are traditionally used but pathway and leads to accumulation of endogenous PpIX are expensive and need regular maintenance. More in significant levels. Kennedy et al[3] first used ALA-PDT convenient is the Nd-YAG laser (690-1100 nm) for the for various malignant skin lesions. The main advantage non-porphyrin photosensitisers. of topical ALA-PDT is the absence of generalized photosensitivity. Limitations of topical ALA are that it Incoherent sources of light used have been slide

157 Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 Nayak CS: Photodynamic therapy in dermatology projectors with or without red filters. Light sources that Basal cell carcinoma:[2-5,16-18] PDT is safe and effective have been developed specifically for PDT include: for the eradication of superficial BCCs. However, 1. Commercially available lamps with appropriate red surgical excision, curettage with electro-dessication, light emission for large surface areas- metal halogen radiotherapy, liquid nitrogen and Mohs micrographic lamp (600-800 nm high power density) surgery are superior to PDT in terms of long-term 2. Short arc xenon lamp (400-1200 nm) recurrence rates. PDT is a good alternative for those medically unfit to undergo surgery or previously treated Indications for PDT with radiation therapy. PDT is ideal where surgery of In 1993, Canada first approved PDT for prophylaxis of extensive lesions could lead to cosmetic disfigurement papillary bladder cancer. Potential indications for or functional impairment. PDT is not effective in photodynamic therapy in dermatology are listed in sclerosing BCC, has shown only moderate results in the Table 2. pigmented variety, but is very valuable for recurrent BCC of Gorlin’s syndrome. “Photodynamic diagnosis” Actinic keratoses:[4-10] Using ALA-based PDT the i.e. delineating the actual borders of BCC using PDT clearance rate of actinic keratoses on the face and scalp helps in ensuring complete surgical removal of tumors. was higher (91%) in comparison with keratoses on the However, the morpheiform variant of BCC cannot be trunk and extremities (45%). Poor clinical response treated with PDT probably due to insufficient porphyrin (<30%) may be attributed to ineffective penetration of synthesis and inadequate penetration of light.[4] ALA and subsequent inadequate production of PpIX. Twenty per cent ALA gave better response in Squamous cell carcinoma:[2] Systemic and topical PDT hyperkeratotic actinic keratoses than 30% ALA. The is a useful diagnostic and adjunctive therapeutic cosmetic results with ALA PDT are excellent.[10] The cure modality in SCC. Diagnostically it helps delineate the rate of actinic keratoses using PDT equals that using exact extent of the tumor. other topical modalities including chemical peels and liquid nitrogen. Kaposi’s sarcoma:[2] Studies to date have shown that response rates with PDT are equal to those with other Bowen’s disease:[11-15] Systemic PDT is very effective. therapeutic modalities in Kaposi’s sarcoma. Topical ALA-PDT gave varied outcomes. ALA-PDT was more effective than liquid nitrogen therapy without its Mycosis fungoides:[2,16,19,20] Various clinical studies have complications of ulceration and infection. PDT is most shown encouraging results for cutaneous suited to widespread, large plaques of Bowen’s disease lymphoproliferative malignancies with photodynamic particularly in anatomically difficult areas of therapy. However, there are no controlled trials yet and involvement. Topical ALA-PDT was found to be more treating lesions locally would probably not prevent new effective than topical 5-fluorouracil in the treatment lesions from coming up. However PDT can be a useful of Bowen’s disease with fewer adverse events. additional treatment modality for patients with therapy-resistant lesions of cutaneous T-cell Table 2: Potential uses of PDT in dermatology lymphoma.[21] Oncologic Non-oncologic Actinic keratoses Psoriasis vulgaris Malignant melanoma:[5,19,22-24] The melanin content of Bowen’s disease Human Papilloma Virus associated dermatoses viz. melanoma markedly reduces penetration of light. Less Superficial squamous and Epidermodysplasia pigmented lesions show better results with PDT. basal cell carcinoma (BCC) verruciformis Nevoid BCC (Gorlin’s) syndrome Condyloma acuminata However, PDT is not really an acceptable modality for Keratoacanthoma Permanent hair epilation melanoma in view of its high propensity for rapid Kaposi’s sarcoma Alopecia areata Cutaneous metastases As an antibacterial in wound spread. healing and acne Cutaneous T cell lymphoma [2,25-29] Tumors in Xeroderma pigmentosum Skin metastases: Palliative PDT of cutaneous Actinic cheilitis metastatic breast carcinoma has been one of the earliest

Indian J Dermatol Venereol Leprol May-June 2005 Vol 71 Issue 3 158 Nayak CS: Photodynamic therapy in dermatology dermatological applications in the history of PDT. The 2. Erythema and edema of the treated area may occur conclusion from various studies is that PDT is helpful after light exposure and may be treated by mild to palliate initial small metastases of breast cancer but topical corticosteroids. is not suitable for the management of advanced or 3. After PDT, there is crusting, scaling accompanied inflammatory carcinoma due to low response rate and by pruritus and then healing takes place by 2 to 8 complications like severe pain and extensive cutaneous weeks. Urea-containing ointments help resolve dry necrosis. crusts and accelerate re-epithelialization. A light overdose may lead to blistering, ulceration and Systemic PDT has been successfully used in the excessive necrosis. treatment of extramammary Paget’s disease resistant 4. Systemic photosensitisers can cause long-lasting to conventional therapy,[18] severe lip dysplasia due to generalized cutaneous photosensitivity and nicotine abuse,[2] and actinic cheilitis.[30] phototoxicity manifesting as burning, stinging, erythema, edema and bullae formation. Sunlight, Non-oncologic uses: In psoriasis of the chronic plaque bright spotlights, photocopy machines, type, both systemic and topical PDT have shown results, photographic flashlights, medical examination lights in some cases equivalent to results with dithranol.[2,31] and operation lamps are to be avoided. Ordinary Though no controlled studies have been done, topical indoor light is safe and may help in photo- 10% ALA ointment applied for 5 hours followed by inactivation of residual drug molecules in the skin. irradiation with 25 J/cm2 from an incoherent light source 5. Photophobia and ocular discomfort may also occur. showed clearing of chronic plaque psoriasis.[32] Verrucae 6. Residual hyper and hypopigmentation have been vulgaris, including recalcitrant ones, laryngeal reported. papillomas and condyloma acuminata have responded 7. Systemically administered HpD may cause vomiting, well to PDT.[2,33,34] PDT has also been used for the nausea, metallic taste and liver toxicity. treatment of recalcitrant and HIV-associated molluscum 8. Systemic PDT is hazardous for porphyria patients contagiosum.[35,36] PDT appears to be an efficient and since porphyrins cross the blood brain barrier, modality for cutaneous vascular malformations with it may precipitate neurological symptoms of acute excellent cosmetic results.[2] Topical HpD and long wave intermittent porphyria. ultraviolet light have led to growth of coarse terminal 9. Following PDT, exacerbation of SLE, photo-Koebner hair in areas of patchy alopecia areata.[2] Hirsutism reaction leading to reactivation of psoriasis and responded to PDT with the advantage that hair follicle malignant melanoma have been reported. damage was highly selective and did not damage the adjacent dermis.[2] However, the merits of PDT outweigh by far its demerits in most cases and it is going to be an important part of COMBINATION OF PDT WITH OTHER MODALITIES the dermatologists’ armamentarium in the future. For better therapeutic efficacy with PDT more clinical, PDT can be effectively combined with surgical biochemical and physical research will be needed. debulking of tumors to make therapy more effective. In combination with adriamycin and mitomycin, it leads REFERENCES to additive anti-tumor effects.

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