MELANOMA The responses of cutaneous melanoma have not

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MELANOMA • The responses of cutaneous melanoma have not been sufficiently beneficial to consider

MELANOMA • The responses of cutaneous melanoma have not been sufficiently beneficial to consider PDT a viable option at the present time. • Although common sense dictates that melanized cells would be relatively resistant to light-based therapies, lutetium texaphyrin, a photosensitizer activated by very deeply penetrating 752 nm red light, did demonstrate the destruction of subcutaneous melanoma metastases in phase I trials. • At present, PDT might only be considered as a final-option, palliative treatment for small cutaneous and subcutaneous metastases of advanced melanoma.

KAPOSI'S SARCOMA • In three HIV-infected patients, Kaposi's sarcoma (KSI) was reported to respond

KAPOSI'S SARCOMA • In three HIV-infected patients, Kaposi's sarcoma (KSI) was reported to respond to systemic PDT consisting of intravenous indocyanin green (two boluses 30 minutes apart) plus irradiation with an 805 nm diode laser. • The lesions irradiated (100 J/cm 2) 10 -30 minutes after the last dose of indocyanin green demonstrated complete clearance; those treated at longer time intervals between injection and irradiation showed only a partial response.

EXTRAMAMMARY PAGET'S DISEASE • In a study of 16 cases of extramammary Paget's disease,

EXTRAMAMMARY PAGET'S DISEASE • In a study of 16 cases of extramammary Paget's disease, 11 of which had received previous treatments (including Mohs micrographic surgery, laser ablation and excision), 8 (50%) showed a complete response at 6 months. However, 3 of these 8 recurred within 1 year, for a durable complete response of 5/16 (31 %). • In this protocol, topical ALA 20% was applied to axillary and anogenitallesions and occluded for 18 -24 hours. • Each lesion received red argon pumped dye laser light (632 nm), followed in some cases by further filtered light (590 -700 nm) irradiation.

PORT-WINE STAINS • As noted previously, given the appropriate photosensitizer, PDT has the ability

PORT-WINE STAINS • As noted previously, given the appropriate photosensitizer, PDT has the ability (via LDL receptor-mediated endocytosis) to induce endothelial cell damage and local vascular collapse. • Initial clinical studies of PDT alone demonstrated reasonable blanching of PWSs, but the treatment was complicated by the development of skin necrosis when both blue and red light sources were employed. • In a series of 118 patients with PWS, one intravenous injection of a purified mixture of six types of porphyrin molecules, followed within 30 minutes by irradiation with a copper vapor laser (578 nm), led to good to excellent clearing in 74% of patients. The highest rate of success was seen in macular PWSs • In one small series, PDT, consisting of oral ALA plus PDL, was investigated as a possible treatment for PWSs. No differance

Investigations are ongoing, as PDT has shown to be the only significant alternative to

Investigations are ongoing, as PDT has shown to be the only significant alternative to photothermal treatments alone as a means of enhancing the rapidity and degree of PWS improvement.

PSORIASIS • In 1937, psoriasis was first reported to respond to PDT consisting of

PSORIASIS • In 1937, psoriasis was first reported to respond to PDT consisting of HPD (i. e. porfimer sodium) plus UV light, with seven patients noting a marked improvement. • Since then, both systemic (e. g. porfimer, BPD-MA) and topical (ALA) photosensitizers, in combination with visible light, have produced partial or complete clearance of psoriatic plaques. • PDT poses an attractive alternative because of the potential for: ü more rapid clearance of lesions ü reduced cumulative exposure to UV irradiation (by using photoactivating doses) and the use of visible light: reduce the carcinogenic risk, when compared to traditional UV irradiation therapies.

ACNE • Both porphyrin expression by naturally occurring Propionibacterium acnes as well as Ppl.

ACNE • Both porphyrin expression by naturally occurring Propionibacterium acnes as well as Ppl. X production occurring primarily within sebaceous glands and hair follicles after topical ALA application have suggested the potential of PDT for diseases of the pilosebaceous unit. • PDT utilizing topical ALA and m. ALA (as well as indocyanine green) may well have an increasing role in the treatment of acne, particularly in patients unable or unwilling to undergo isotretinoin therapy.

HUMAN PAPILLOMAVIRUS INFECTIONS • Systemic and topical PDT have led to lesion regression in

HUMAN PAPILLOMAVIRUS INFECTIONS • Systemic and topical PDT have led to lesion regression in rabbit models. In addition, some in-vitro studies have pointed to a direct antiviral effect of PDT. • As with any cutaneous tumor, topical PDT would be preferred for its lesion specificity and limited photosensitivity. • In one study, a maximal condylomata: normal skin Pp. IX fluorescence ratio was detected at 2 hours, suggesting that virally infected cells could be preferentially targeted by PDT at this same time point. • Lastly, because mucosal lesions (i. e. condylomata) typically do not have associated hyperkeratotic scale (which inhibits drug penetration) and cutaneous lesions (i. e. verrucae) are characteristically keratotic, more variable responses to topical PDT would be anticipated with verrucae.

OTHER INFECTIOUS DISEASES • including Staphylococccus aureus and Streptococcus pyogenes • ü IN ONE

OTHER INFECTIOUS DISEASES • including Staphylococccus aureus and Streptococcus pyogenes • ü IN ONE PATIENT WITH CUTANEOUS LEISHMANIASIS due to Leishmania donovani five lesions, recalcitrant to treatment with repeated courses of systemic sodium stibogluconate, were treated with topical m. ALA PDT. All treated sites demonstrated clinical clearance with an excellent cosmetic result. ü Furthermore, three additional lesions in the same patient, previously recalcitrant to treatment with topical paromomycin sulfate, were also successfully treated utilizing the same PDT protocol.

PHOTODAMAGE • improvements in fine lines, sallowness and mottled pigmentation

PHOTODAMAGE • improvements in fine lines, sallowness and mottled pigmentation

PREOPERATIVE CONSIDERATIONS • Evaluation of clinical exclusion criteria: ü Porphyria or other relevant photosensitivity

PREOPERATIVE CONSIDERATIONS • Evaluation of clinical exclusion criteria: ü Porphyria or other relevant photosensitivity disorders ü Documented allergy to the photosensitizer, similar chemical structures or trace manufacturing agents ü History of hepatic disease or concurrent medications subject to hepatic metabolism ü And a prior or current herpes simplex virus (HSV) infection in or near the treatment site, especially if there is a history of HSV flares with UV light exposure.

 • Medications known to cause phototoxicity reactions in combination with UV light should

• Medications known to cause phototoxicity reactions in combination with UV light should not be activated by the visible wavelengths used in PDT. • Baseline liver function tests should be obtained prior to systemic photosensitizer administration, particularly in those patients with a history of or suspected hepatic disease. o Most PDT systems can create painful stimuli, described by patients as ranging from 'warmth' to 'needle pricks' to intense 'burning pain'. o Pain reduction during irradiation may be accomplished with local ice packs, cool air, or local anesthetic injection. • Local anesthetics should be administered without epinephrine in order to maintain tissue oxygen delivery during irradiation.

 • Approved ALA PDT, which utilizes blue light for the treatment of AKs,

• Approved ALA PDT, which utilizes blue light for the treatment of AKs, requires the use of opaque protective goggles as well as placing the face within a relatively confined space illuminated by bright blue light. • Some patients may feel' claustrophobic' or find this a stimulus for a panic attack.

 • Patients should be carefully advised regarding the risk and duration of local

• Patients should be carefully advised regarding the risk and duration of local or generalized photosensitivity. • UVA/B sunscreens will not protect against photodynamic burns caused by visible wavelengths. • Although physical sunscreens (Zn 02, Ti 02, Fe 2 o 3) should provide greater protection into the visible spectrum, patients must be advised to cover up with appropriate clothing, wear protective goggles, and simply avoid bright light from any source.

TECHNIQUE • Before any PDT is undertaken, adequate documentation of the lesions to be

TECHNIQUE • Before any PDT is undertaken, adequate documentation of the lesions to be treated, a full history and informed consent should be obtained. • Preoperative photographs are helpful to …. • PDT should be carried out in an appropriate clinical setting; it should provide for low light levels (preferably no windows and a dimmer switch or lamp), cooling and ventilating for the heat generated by the light source, and a room whose size is adequate for the necessary equipment. • Like any similar situation, the uncomfortable sensations caused by PDT can evoke vasovagal responses. These are largely preventable by instructing patients to eat a moderate meal before therapy, and by prone or supine positioning during intravenous infusions and irradiation.

TOPICAL PDT TECHNIQUE • The current FDA-approved PDT system for the treatment of AKs

TOPICAL PDT TECHNIQUE • The current FDA-approved PDT system for the treatment of AKs incorporates a single-use 20% ALA solution applicator (Levulan® Kerastick®) and a blue (417 nm) non-coherent light source (BLU-U®). • The area to be treated may initially be cleansed with acetone to remove sebum and facilitate ALA absorption or subjected to microdermabrasion to remove the stratum corneum. • The sponge applicator is applied thrice to the desired lesions and allowed to dry after each application. The manufacturer estimates that one applicator is adequate for treating up to 250 lesions. • Initial incubation times of 18 to 24 hours were previously the norm; however, to reduce associated pain, most practitioners now perform irradiations within 1 to 3 hours after ALA application.

 • Irradiation occurs for 16 minutes and 40 seconds. • The intensity of

• Irradiation occurs for 16 minutes and 40 seconds. • The intensity of pain typically becomes maximal towards the end of the treatment. Distraction using a radio or television and skin cooling using a fan should make the patient more comfortable. • If the patient complains of too much discomfort, therapy can be stopped and continued after a short break. • Of note, pulsed light sources complete irradiation more quickly, irradiate small areas, allow inherent rest periods during treatment, and cause less discomfort for patients, but recent work has shown that pulsed light may be less effective than continuous wave sources.

m. ALA PDT • Administration of m. ALA (Metvix@) PDT is similar, except for

m. ALA PDT • Administration of m. ALA (Metvix@) PDT is similar, except for tumor preparation. Without anesthesia, tumors are gently curetted to remove crusts and the superficial tissue of any bulky lesion. • The m. ALA cream (160 mg/g) is then immediately applied under occlusion for 3 hours. • After gently removing the cream with cotton gauze, the patient is positioned an appropriate distance from the light source (Cure. Light®). • This therapy is FDA-approved for non-hyperkeratotic AKs of the face and scalp.

SYSTEMIC PDT • Systemic PDT involves oral or intravenous administration of the drug or

SYSTEMIC PDT • Systemic PDT involves oral or intravenous administration of the drug or prodrug. • Porfimer, BPD-MA, Sn. ET 2 or m. THPC can be given by a slow, fixedrate infusion; the time until light application is typically determined with reference to the initiation of the intravenous infusion. • When given orally, ALA powder is mixed with orange juice and given either as a single oral bolus or fractionated into 20 mg/kg doses, imbibed hourly. The time until light application is determined with reference to the last oral dose. • The patient should be kept in a low-light room to prevent both acute phototoxicity and photobleaching. Because of their rapid and broad distribution, systemic photosensitizers do require more attention to normal skin shielding during irradiation. • Patients are given goggles for ocular protection and instructed to avoid bright light exposure.

POSTOPERATIVE CARE • Immediately after PDT, the treatment sites develop erythema and edema, often

POSTOPERATIVE CARE • Immediately after PDT, the treatment sites develop erythema and edema, often leading to a peau d'orange appearance • Pain typically reduces dramatically with cessation of irradiation. Postoperative pain is usually easily controlled with acetaminophen or non-steroidal antiinflammatory drugs, but some individuals may require opioid analgesics. • The patients should again be advised how to avoid photosensitivity reactions by covering themselves with clothing. • Those receiving systemic agents should use eyewear that blocks the appropriate wavelengths faithfully until the risk of photosensitivity is minimal.

Wound Healing • More superficial epithelial conditions (e. g. AKs, psoriasis, SCCs in situ)

Wound Healing • More superficial epithelial conditions (e. g. AKs, psoriasis, SCCs in situ) may crust and then peel, with newly healed skin appearing within 1 -2 weeks. • With deeper dermal conditions and photo sensitizers that cause more vascular injury, treated sites first blister or turn gray, then deeper ulcerative wounds develop requiring more prolonged healing times (weeks to months). • Patients should keep the wounds moist by applying a topical antibiotic or white petrolatum two to three times a day. • Wound infections may occur, but at no greater frequency than with other wounds healing by second intention. Therefore, unless there is a strong propensity to wound infections, patients should only receive antibiotics for identified infections. • Patients with a history of HSV infection should receive antiviral prophylaxis if PDT will be administered to the site of a prior infection or an

COMPLICATION Cutaneous Photosensitivity and Photophobia • The main concern and limitation of systemic administration

COMPLICATION Cutaneous Photosensitivity and Photophobia • The main concern and limitation of systemic administration is prolonged generalized cutaneous photosensitivity, lasting up to 2 or 3 months for porfimer sodium, but as short as several days for BPD-MA or 1 day for oral ALA. • The action spectrum for the associated phototoxicity lies within the visible (blue-green and red) portion of the electromagnetic spectrum. • Patients must clearly understand that sunscreens that block UV light are ineffective protection. • Physical sunscreens (Zn 02 Fe 203 or Ti 02) and dihydroxyacetone (DHA)-induced 'tans' may provide some protection, but the best option is to cover all skin surfaces with tightly woven dark clothing.

 • Patients should also avoid any intense visible light source, such as phototherapy

• Patients should also avoid any intense visible light source, such as phototherapy units, tanning beds, bright medical examination lamps, operating theater lights or pulse oximeters. o Low indoor lighting is usually not sufficient to trigger a reaction. • Photo toxic reactions to systemic ALA are characterized by mild to moderate erythema and edema followed by desquamation 48 -72 hours later. • Photo toxic reactions secondary to BPD-MA or porfimer begin as rapidly, but resolve more slowly. • Topical photosensitizer delivery will usually not lead to sufficient systemic absorption to cause a generalized photosensitivity reaction. Even local photosensitivity due to topical photosensitizer application is rare, but can occur and should be prevented by opaque clothing or dressings.

PDT has been reported to reactivate photosensitive conditions such as lupus, and the Koebner

PDT has been reported to reactivate photosensitive conditions such as lupus, and the Koebner phenomenon was described after PDT treatment of a superficial SCC in a patient with psoriasis.

PAIN • This is the most commonly reported side effect of PDT and it

PAIN • This is the most commonly reported side effect of PDT and it can vary from a slight ache to severe pain. The degree of pain depends on the size and anatomic site of the lesion being treated as well as the particular photosensitizer. • Comparative study of m. ALA versus ALA found that the associated pain was less severe with m. ALA, and the explanation was greater absorption of ALA by cutaneous nerves.

CONSTITUTIONAL SYMPTOMS • Nausea, emesis, headache and flu-like symptoms. • Virtually all macrocyclic photosensitizers

CONSTITUTIONAL SYMPTOMS • Nausea, emesis, headache and flu-like symptoms. • Virtually all macrocyclic photosensitizers are subject to hepatic metabolism, and liver toxicity has occurred with HPD (porfimer sodium). • Large (30 -40 mg kg) oral doses of ALA may cause a transient (1 -3 weeks), dose-dependent elevation of hepatic enzyme and bilirubin levels. • However, to date there has been no evidence of permanent liver damage or changes in neurologic function or hematologic indices after oral ALA administration at these doses. • More recent experience suggests that ALA dose fractionation (20 mg kg given at hourly intervals) circumvents the elevation of hepatic enzymes.

LOCAL SITE REACTIONS • Edema : systemic corticosteroid therapy if essential • Crusting and

LOCAL SITE REACTIONS • Edema : systemic corticosteroid therapy if essential • Crusting and occasional blistering : topical PDT • Necrosis, ulceration and eschar formation: • Treatment site pruritus : systemic PDT common , both topical and systemic PDT • Postinflammatory hyper or hypopigmentation • Hypertrophic scarring: • Permanent alopecia prone anatomic sites

ALLERGIC CONTACT DERMATITIS • Single case of allergic contact dermatitis: topical ALA • Single

ALLERGIC CONTACT DERMATITIS • Single case of allergic contact dermatitis: topical ALA • Single case of transient urticaria : during an HPD infusion

MUTAGENIC POTENTIAL • Although visible light carries no risk of cutaneous carcinogenesis, concern has

MUTAGENIC POTENTIAL • Although visible light carries no risk of cutaneous carcinogenesis, concern has been raised about the potential genotoxicity of PDT-induced oxygen free radicals. • There is one report of melanoma developing within the treatment site after multiple PDT sessions for keratinocytic neoplasia. • Although the authors proposed that the immunosuppression caused by PDT might act as a tumor promoter, the location of the treatment site within a heavily sun-exposed area makes the association more likely fortuitous. • In vitro studying result, suggesting that PDT did not produce cell death through chromosomal damage. • The current data suggest that there is no increased risk of secondary tumors, thus offering the advantage of repeated treatments.

FUTURE DIRECTIONS • The future of this highly promising diagnostic and therapeutic technique will

FUTURE DIRECTIONS • The future of this highly promising diagnostic and therapeutic technique will depend upon the intricate relationship between technology and clinical medicine. • Clinicians should expect advances in light delivery (automated sources with realtime monitoring of dosimetry), photosensitizer development (e. g. indium methyl pyrropheophorbide, a chlorin derivative capable of topical delivery), basic research to elucidate in detail the mechanism of photodynamic action in vivo, and clinical research to establish the safety and efficacy of new photosensitizers as well as to compare proven photosensitizers against standard therapies. • Ongoing evaluation of the role of PDT in the treatment of pilosebaceous tumors, lichen planus, morphea, port-wine stain vascular malformations and hirsutism (photodynamic tricholysis), to name just a few.