Photodynamic Therapy in Dermatology:
`An Update on Applications and Outcomes
`Mollie A. MacCormack, MD*,†
`
`Photodynamic therapy is a relatively new and rapidly evolving therapeutic option in der-
`matology. Initially used for the treatment of actinic damage and nonmelanotic skin cancer,
`more recent work indicates efficacy in the treatment of a wide range of conditions, such as
`acne, infectious processes, cutaneous T-cell lymphoma, and photorejuvenation, among
`others. This article provides a comprehensive review of applications and outcomes that use
`topical photodynamic therapy in the treatment of dermatologic disease.
`Semin Cutan Med Surg 27:52-62 © 2008 Elsevier Inc. All rights reserved.
`
`KEYWORDS photodynamic therapy, aminolevulinic acid, methyl aminolevulinate, actinic kera-
`toses, basal cell carcinoma, squamous cell carcinoma in situ
`
`P hotodynamic therapy (PDT) harnesses the power of light
`
`and oxygen to enact biologic change. In its infancy, the
`use of PDT in the treatment of dermatologic disease was
`limited due to the prolonged and pronounced photosensitiv-
`ity resulting from systemic photosensitizing agents. How-
`ever, in the early 1990s Kennedy and Pottier described the
`u s e o f topical 5-aminolevulinic acid (ALA) to create endog-
`enous protoporphyrin IX (PpIX) from which came a limited,
`localized, photodynamic response.1 With this development,
`many of the early limitations of PDT were alleviated, and the
`treatment became much more convenient. Early application
`focused primarily on the treatment of dysplastic and neoplas-
`tic disease; however, during the past few years, the versatility
`of PDT has been more fully realized, and it is now also being
`used to treat a wide variety of inflammatory and infectious
`processes. As the history of PDT has previously been exten-
`sively reviewed,2-5 this article will focus on current uses with
`an emphasis on the most commonly used photosensitizing
`agents and recent developments in practical application.
`
`Mechanism of Action
`The basic premise of PDT is quite simple. In the presence of
`oxygen a photosensitizing agent, either endogenous or exog-
`enous, is exposed to light resulting in the creation of activated
`intermediates, primarily singlet oxygen. Singlet oxygen is a
`
`*Harvard Medical School, Boston, MA.
`†Director of Dermatologic Surgery, Lahey Clinic, Burlington, MA.
`Address reprint requests to Mollie Maccormack, MD, Lahey Clinic, Depart-
`ment of Dermatology, 41 Mall Road, Burlington, MA 01805. E-mail:
`Mollie.maccormack@lahey.org
`
`very reactive molecule that can damage many components of
`the target cell,
`including mitochondria resulting
`in cell
`death.6,7 Supplementing this direct assault are indirect path-
`ways of cellular destruction such as the recruitment of in-
`flammatory cells, increased immune response and vascular
`compromise.8 Singlet oxygen can also destroy the photosen-
`sitizing agent itself preventing further action, a process re-
`ferred to as photobleaching.
`The effectiveness of PDT depends on (1) the photosensi-
`tizer used, its ability to selectively penetrate diseased tissue,
`and the duration of application; (2) the activating
`light
`source, its ability to penetrate to the desired target, and its
`duration of exposure; and (3) the type of target cells and their
`oxygenation status. To be effective, the damage resulting
`from PDT must surpass cellular repair mechanisms, a feature
`referred to as the minimum photodynamic dose.
`
`Aminolevulinic Acid (ALA)
`Currently Food and Drug Administration (FDA) approved
`for the treatment of actinic keratoses, ALA (Levulan®: DUSA
`Pharmarceuticals, Wilmington, MA) is the only topical pho-
`tosensitizing agent available for dermatologic use
`in the
`United States. ALA is a hydrophilic, low molecular weight
`molecule that is absorbed readily through abnormal but not
`through normal keratin.9 Once absorbed by epidermal or
`appendageal cells ALA is converted to PpIX, a potent photo-
`sensitizer. Due to of limited supplies of iron, a necessary
`catalyst for ferrochelatase, recipient cells are unable to com-
`plete the final stage of conversion of PpIX to heme leading
`to PpIX accumulation. With short application times (⬍4
`
`52
`
`1085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
`doi:10.1016/j.sder.2007.12.001
`
`

`

`Photodynamic therapy in dermatology
`
`53
`
`hours), PpIX production is largely limited to the target site;
`however, with longer application periods, a larger area of
`reaction may develop.10 Photosensitization typically resolves
`within 24 hours after application is completed. Maximal light
`absorption is seen at 409 nm, and smaller peaks occur at 509
`nm, 544 nm, 584 nm, and 635 nm. Existing FDA approval is
`based on a 14- to 18-hour application period; however, stud-
`ies have demonstrated efficacy with shorter incubation peri-
`ods (1 hour) that are more convenient for both patient and
`practitioner.11,12
`
`Methyl Aminolevulinate (MAL)
`Methyl aminolevulinate (MAL) (Metvix®; Photocure ASA,
`Oslo, Norway) is the methyl ester of ALA. Although approved
`by the FDA in 2004 for the treatment of actinic keratoses, it is
`not currently available in the United States. Unlike ALA, MAL
`is provided as a 160 mg/g cream designed to be applied under
`occlusion for 3 hours followed by red light activation (570-
`670 nm for a total dose of 75J/cm2), at which point complete
`photobleaching should have occurred. More lipophillic than
`ALA, MAL is felt to exhibit increased tumor/diseased skin
`specificity when compared with ALA.13 Initially MAL also
`was expected to exhibit improved tissue penetration and thus
`greater efficacy when compared with ALA; however, recent
`studies suggest similar levels of effect or perhaps even in-
`creased activity of ALA.14-16
`
`Light Sources
`Both ALA and MAL lead to the production of PpIX which, as
`previously noted, displays a large peak in absorption spectra
`at 409 nm, with much smaller peaks at 509 nm, 544 nm, 584
`nm and 635 nm. While blue light such as that emitted by the
`Blu-U® (DUSA Pharmaceuticals, Wilmington, MA) or Om-
`nilux Blue™ (Photo Therapeautics Inc., Carlsbad, CA) takes
`advantage of the largest absorption spike at 417 nm, it is
`limited by depth of penetration to about 1.5 to 2 mm. Red
`light (⬎600 nm) requires higher energy levels to achieve the
`same effect (because of the lower PpIX light absorption at
`longer wavelengths), but has the advantage of being able to
`penetrate deeper (approximately 8-10 mm). However, this
`deeper penetration can be limited be melanin.17 Filtered red
`or green noncoherent light sources are commonly used in
`Europe, whereas in the United States longer wavelength light
`sources include diode and pulsed dye lasers as well as intense
`pulsed light (IPL).
`
`Dermatologic
`Clinical Applications
`Actinic Keratoses
`ALA and Actinic Keratoses
`First described by Kennedy and coworkers,9 the use of ALA–
`PDT to treat actinic keratoses has become the most frequent
`and well studied dermatologic application of PDT in the
`United States (Table 1).18-41 Although the earliest studies
`
`used an oil in water formulation of ALA that required occlu-
`sion for penetration,18,23 in 1999, FDA approval was granted
`for a treatment protocol that involves application of 20% ALA
`solution to individual actinic keratoses for a period of 14 to
`18 hours followed by a 16-minute, 40-second exposure to
`blue light (417 ⫾ 5 nm) for a total dose of 10 J/cm2. A second
`treatment, if needed, is performed at week 8. Complete re-
`sponse of nonhyperkeratotic actinic keratoses after one treat-
`ment is approximately 65%, increasing to 85% after the sec-
`ond treatment.10,35 A subsequent phase IV clinical trial found
`recurrence rates of 19% at 12 months.40 Practical consider-
`ations led to a number of modifications to the aforemen-
`tioned treatment protocol such as much abbreviated incuba-
`tion periods (1 hour)11 and broad application in lieu of spot
`treatment.29 Broad application, short contact (1 hour), ALA–
`PDT activated by blue light has been found to be both more
`effective and more easily tolerated than 0.5% fluorouracil
`cream applied 1 to 2 times daily for 4 weeks.12 The safety of
`broad area application is supported by an animal study pub-
`lished by Bissonette and coworkers in which hairless mice
`were treated weekly with either ALA, blue light alone or
`ALA–PDT. No carcinogenic potential was seen in any
`group.42 ALA–PDT for the treatment of actinic keratoses has
`also been described utilizing IPL with 42-68% improvement
`after one treatment, however, these studies tend to be small
`and not well controlled.36,37
`
`MAL and Actinic Keratoses
`A number of prospective randomized studies have been pub-
`lished evaluating the use of MAL–PDT for the treatment of
`actinic keratoses (Table 1). The most commonly used proto-
`col involves light curettage of lesions, application of a thick
`layer of MAL cream left under occlusion for at least 3 hours,
`followed by exposure to noncoherent red light (570-670 nm,
`75 J/cm2), with repeat treatment at 1 week. Complete re-
`sponse ranges from 69% to 91%31; with only a single treat-
`ment this decreases to 70%.38 These numbers are similar to
`those seen with cryotherapy (complete reponse 68-75%);
`however, many feel that MAL–PDT is superior in terms of
`cosmetic outcome and patient satisfaction.21,30,39 Superior
`outcomes have also been described in comparison to 5-flu-
`orouracil cream applied twice daily for 3 weeks.41 When
`compared with PDT using 20% ALA cream, similar efficacy
`was seen in both groups; however, ALA–PDT was noted to be
`more uncomfortable for patients then MAL–PDT.43
`
`Nonmelanotic Skin Cancer
`Basal Cell Carcinoma
`Although not currently approved by the FDA, numerous
`studies have documented the efficacy of PDT in the treatment
`of basal cell carcinoma.1,20,44,45 Most early studies used 20%
`ALA in an oil and water emulsion with red light activation;
`however, more recent work has focused on 20% ALA solu-
`tion and MAL.46,47 As expected, superficial basal cell carci-
`noma (sBCC) seems to respond best, with reported complete
`response rates ranging from 50 to 100%46-48 whereas com-
`plete response of nodular tumors ranges from 10% to 100%
`
`

`

`54
`
`M.A. MacCormack
`
`Table 1 Studies on the Use of Topical ALA/MAL PDT for the Treatment of Actinic Keratoses
`Lesions
`Photosensitizer,
`Light Source
`Treated
`Time (hours)
`(nm)
`10
`ALA, 3 to 6
`Tungsten > 600
`9
`ALA, 4 to 8
`Tungsten unfiltered
`50
`ALA, 6 to 8
`ArDL 630
`
`Results
`90% CR, 10% NR
`100% CR
`100% CR (multiple treatments)
`
`Reference
`Kennedy 19909
`Wolf 199318
`Calzavara-Pinton
`199519
`Fijan 199520
`Szeimies 199621
`
`43
`36
`
`ALA, 3% DFO, 20 Halogen 570 to 690
`ALA, 6
`Red 580 to 740
`
`Fink-Puches
`199722
`
`Jeffes 199723
`
`Kurwa 199924
`
`Dijkstra 200125
`Varma 200126
`Jeffes 200110
`
`Ruiz-Rodriguez
`200227
`Szeimies 200228
`
`Goldman 200329
`Freeman 200330
`Pariser 200331
`Smith 200312
`
`251
`
`ALA, 4
`
`240
`
`–
`
`4
`111
`70
`
`0, 10, 20, 30%
`ALA, 3
`ALA, 4
`
`ALA, 8
`ALA, 4 to 6
`ALA, 14 to 18
`
`38
`
`ALA, 4
`
`54 MAL, 3
`
`ALAs, 15 to 20
`35
`360 MAL, 3, 2 rx
`260 MAL, 3, 2 rx
`148
`ALAs, 1
`
`Alexiades 200332
`
`3622
`
`ALAs
`3 w/occlusion
`
`14 to 18 w/o
`
`UVA ⴙ/or FSVL ⴙ/or FL
`>515, >530, 570,
`>610
`ArDL 630
`
`Red 580 to 740
`
`Violet 400 to 450
`Red 600 to 730
`Blue 417 ⴞ 5
`
`IPL 590 to 1200
`w/cutoff filter 615
`Red 570 to 670
`
`Blue 417 ⴞ 5
`Red 570 to 670
`Red 570 to 670
`Blue 417 ⴞ 5 or PDL
`595
`PDL 595
`
`Dragieva 200433
`
`44 (OT) ALA, 5
`
`Red 570 to 650
`
`81% CR
`71% CR (lesser response seen
`on hands)
`Face, scalp, and Neck: 91 to
`100% CR* Forearms and
`Hands: 33% to 51% CR†
`91% CR-face and scalp 45%
`CR-trunk and extremities
`73% reduction in lesional area –
`hands
`25% CR, 75% PR
`1 rx - 77% CR, 3 rx - 100% CR
`1 rx - 66% CR, 17% PR 17% NR
`2 rx - 85% CR, 6% PR 9% NR
`1 rx - 76% CR 2 rx - 91% CR
`
`71% CR Face, 61% CR Scalp,
`75% CR other
`94% CR, 6% PR
`91% CR
`82% CR
`Blue light: 50% CR, 25% PR
`PDL: 8% CR, 33% PR
`10 days
`Head – 99.8% CR, Exts – 75.2%
`CR
`Trunk – 77% CR
`8 months
`Head – 87.7% CR, Exts – 100%
`CR
`Trunk – NR
`Face – 96% CR, 86% CR at 3
`month
`90% CR
`1 rx - 91% CR, 2 rx - 83% CR
`
`Follow-Up
`(mos)
`18
`3 to 12
`24 to 36
`
`3 to 20
`3
`
`36
`
`2
`
`6
`
`3 to 12
`13‡
`4
`
`3
`
`3
`
`1
`3
`3
`1
`
`8
`
`3
`
`4
`3
`
`3
`5
`
`3
`3
`
`6
`12
`
`Dragieva 200434
`Piacquadio
`200435
`Avram 200436
`Touma 200411
`
`62 (OT) MAL, 3, 2rx
`1403
`ALAs, 14 to 18
`
`Red 600 to 730
`Blue 417 ⴞ 5
`
`–
`>72
`
`ALAs, 1
`ALAs, 1, 2, or 3
`
`IPL w/560 filter
`Blue 417 ⴞ 5
`
`Kim 200537
`Tarstedt 200538
`
`ALA, 4
`12
`413 MAL, 3, 1-2rx
`
`IPL 555 to 950
`Red 634 ⴞ 3
`
`Morton 200639
`Tschen 200640
`
`758 MAL, 3, 1-2 rx
`968
`ALAs, 14 to 18
`
`Red Light
`Blue 417 ⴞ 5
`
`68% CR
`CR: 1 month - 85% to 96%, 5
`months: 87% to 94%
`50% CR
`Thin Lesion, 93% CR 1 rx, 89%
`CR 2 rx Thick Lesion, 70% CR
`1 rx, 88% CR 2 rx
`88% CR Face, 83% CR Scalp
`1 rx: 76% CR at 1 month, 72%
`CR at 2 month 2 rx: 86% CR
`at 4 month, 78% CR at 12
`month
`Perrett 200741
`6
`89% CR
`Red 570 to 670
`9 (OT) MAL, 3, 2 rx
`ALA, 20% 5-aminolevulinic acid oil in water emulsion; MAL, methyl aminolevulate 160 mg/g; ALAs, 20% 5 aminolevulinic acid solution; CR, complete
`response; NR, no response; PR, partial response; rx, treatment; ArDL, Argon pumped tunable dye laser; DFO, desferrioxamine; UVA, ultraviolet
`A; FSVL, full spectrum visible light; FL, filtered light; IPL, intense pulsed light device; PDL, pulsed dye laser; OT, organ transplant patients.
`*Best results seen with UVA ⴙ FSVL.
`†Best results seen with FSVL ⴙ FL.
`‡28% recurrence rate.
`
`

`

`Photodynamic therapy in dermatology
`
`55
`
`(multiple treatments were necessary to achieve the higher
`figure).18,45,47,49 Pigmented lesions in particular tend to re-
`spond poorly because of interference by melanin.19 Recur-
`rence is an issue for all tumor types, reaching as high as 44%
`at 19 months for sBCC50 and 57% at 3 months for nBCC20
`treated with ALA and 18% at 12 to 24 months for lesions
`treated with MAL.26,45 Vinciullo and coworkers treated 148
`“difficult-to-treat” BCCs, which they defined as large lesions,
`lesions in the H-zone, or BCC in patients with high risk of
`surgical complications, with MAL-PDT. Initial complete re-
`sponse was 89% at 3 months; however, by 24 months it had
`decreased to 78%.51
`One of the limitations of PDT is that both the photosensi-
`tizing agent and the light source may have difficulty reaching
`deeper areas of disease. This limitation is evidenced by a
`2003 study in which the probability of 1-year control was
`85% for BCC less than 1.5 mm deep but decreased to 75%
`when lesions 3 mm thick were included.52 Various attempts
`have been made to ameliorate this phenomenon, including
`pretreatment debulking,44,53 multiple treatments,19 the use of
`fractionated light delivery to limit photobleaching,54 intersti-
`tial light delivery,55 intralesional injection of ALA,56 and the
`use of PDT as an adjunct to Mohs surgery.57 A recent pilot
`study by Berroeta and coworkers was designed to compare
`minimal curettage followed by ALA–PDT (20% ALA cream
`applied under occlusion for 6 hours followed by 620-nm
`laser activation 125 J/cm2) with surgical excision for primary,
`⬍2 cm, well-defined, nodular, BCCs in low risk anatomic
`areas. Altough cosmesis was equivalent between the two
`groups, 17% more tumors cleared with surgical excision and
`PDT was deemed to be the more painful intervention. Based
`on these results the authors concluded that for now, surgery
`remains the first treatment option for nodular BCCs.58 A
`number of studies have evaluated the use of PDT in the treat-
`ment of nevoid BCC syndrome. Treatment parameters vary,
`but reported efficacy ranges from 67 to 100% for sBCC and
`31 to 98% for nevoid BCC.25,59-61
`
`Squamous Cell Carcinoma and
`Squamous Cell Carcinoma In-Situ
`Because of limitations in the ability to treat deep-set disease,
`PDT is not currently recommended as a treatment modality
`for invasive SCC.62 Many studies, however, have shown good
`effect with the use of PDT to treat in situ disease. Initial cure
`rates typically range from 60% to 100% with the largest mul-
`ticenter trial (225 patients) revealing a 93% cure rate at 3
`months, decreasing to 80% at 12 months using MAL–PDT.63
`In comparison, the same study found complete response
`rates of 86% and 67% with cryotherapy and 83% and 69%
`with 5-fluorouracil at 3 and 12 months respectively. Case
`reports have also described effective treatment of subungual
`Bowen’s disease with ALA PDT,64,65 in situ disease in patients
`with epidermolysis bulosa,66 and an ambulatory system de-
`signed to facilitate treatment.67
`Numerous articles have described the use of PDT for the
`treatment of erythroplasia of Queyrat.68-70 Unfortunately, re-
`sults have been somewhat disappointing with fairly low ini-
`
`tial response rates, high recurrence, and (in 1 case) progres-
`sion to invasive disease.69
`
`Acne
`In the era of increasing antibiotic resistance and increasing
`bureaucratic regulation of systemic retinoid use, an alterna-
`tive and effective acne treatment is desirable. The initial the-
`ory behind the use PDT for acne centered on the endoge-
`nous production of porphyrins by bacteria, such as
`Propionibacterium acnes, as a byproduct of their metabo-
`lism. By exposing the skin to the appropriate wavelength of
`light, these porphyrins can be activated leading to bacterial
`elimination.71,72 Many investigators have attempted to capi-
`talize on this phenomenon with varying levels of success
`(Table 2).73-89 Blue light alone has been demonstrated to im-
`prove both inflammatory and comedonal lesions.73,74,77,79,82
`Because ALA accumulates not only in malignant cells but also
`in sebaceous glands, it was hypothesized that an even-greater
`effect could be obtained by applying either ALA or MAL to
`the skin before light exposure. The earliest studies involved
`application of ALA for 3 or 4 hours followed by exposure to
`red/visible light.75,76 Although clearly effective, side effects
`such as an acneiform flare at day 3 to 4, erythema, hyperpig-
`mentation, and exfoliation were pronounced. Modifications
`followed, including decreased time of photosensitizer appli-
`cation,77,85 and use of blue light or IPL as a light source.80,84
`As seen in Table 2, although many different regimens have
`been tried, no one single protocol has proven to be the best.
`Of note, Wiegel and Wolff did compare ALA and MAL ap-
`plied for 3 hours under occlusion followed by red light acti-
`vation. Although no significant difference was noted in terms
`of efficacy (both led to a 59% in inflammatory lesions at week
`12), ALA was noted to cause more side effects such as edema,
`erythema, and scale.15
`
`Sebaceous Hyperplasia
`Accumulation of ALA in sebaceous glands led not only to its
`use in the treatment of acne but also prompted investigation
`of its use for the treatment of sebaceous hyperplasia. Various
`light sources have been used ranging from halogen ⬎620
`nm,90 to blue light,91 to pulsed dye laser (595 nm) (PDL) to
`IPL.92 Application time of ALA ranges from 1 to 4 hours, and
`number of treatments ranges from 1 to 6. The most effective
`results seem to be those described in studies by both Alster93
`and Richey.89 Alster applied ALA for 1 hour followed by PDL
`activation. Seven of 10 patients cleared in 1 treatment, 3
`cleared after 2. Side effects included transient erythema and
`crusting. Richey treated patients with 45 minute-1 hour of
`ALA, followed by blue light for 3 to 6 treatments. Clearance
`was 70% after 6 months; however, 10-20% recurrence was
`noted 3 to 4 months after the last treatment. Side effects were
`similar to those previously noted. Clearance of a nevus seba-
`ceous was obtained by Dierickx and colleagues after 13 ses-
`sions using 20% ALA applied for 4 hours with 630 nm argon
`laser activation.94
`
`

`

`56
`
`M.A. MacCormack
`
`Results
`Improvement in acne and oil production
`
`Blue: 45% improvement comedones, 63% improvement
`inflammatory lesions. Blue and Red: 58% improvement
`comedones, 76% improvement inflammatory lesions
`
`Flare noted 3 to 4d after rx. Significant improvement
`noted. Improvement persisted >10 weeks after single
`rx and >20 weeks after 4 rx. Side effects included
`erythema, hyperpigmentation, exfoliation
`Reduction in new acne lesions noted for 6 months. Side
`effects included erythema, hyperpigmentation,
`exfoliation
`Blue light alone:
`25% improvement acne severity
`40% decrease papules
`65% decrease pustules
`62% decrease comedones
`ALA ⴙ Blue light:
`32% improvement in acne severity
`68% decrease papules
`61% decrease pustules
`62% decrease comedones
`31% decrease in inflammatory lesions seen after 2nd rx
`and at 3 week f/u
`52% mean improvement with greatest benefit seen in
`comedonal and papulopustular lesions, nodulocystic
`acne worsened
`66%% of patients had at least 50% improvement, no
`significant difference noted between groups, side
`effects included erythema and peeling
`
`21% improvement in comedones at week 4 and 8, 36%
`improvement inflammatory lesions at week 4 and 8.
`Control arm using 1% clindamycin bid had 14%
`improvement in both comedonal and inflammatory
`lesions
`Statistically significant decrease inflammatory lesions
`seen at week 8, persisted to week 12, no change
`comedonal lesions
`
`Table 2 Studies on the Use of Photodynamic Therapy for Acne
`Reference
`Patient No.
`Photosensitizer
`None
`Meffert 199073
`
`Papageorgiou 200074
`
`107
`
`None
`
`Hongcharu 200075
`
`22 (Truncal Acne)
`
`Itoh 200176
`
`Goldman 200377
`
`13
`
`22
`
`ALA 20% occluded
`x 3 hours
`
`ALA 20% occluded
`x 4 hours
`
`None or ALA 20%
`soln x 15 min
`
`Light Source (nm)
`Blue 400 to 420 10 min x 10 exposures
`(cumulative dose –325J/cm2)
`Blue 415 ⴙ 20/-15, or Blue and Red
`415 & 660 ⴞ 10, 15 min qd x 12
`weeks (cumulative dose 320 J/cm2
`blue, 202 J/cm2 red)
`Red 550 to 700 (150 J/cm2) ½ had
`single rx, ½ had rx 1x/wk x 4 weeks
`
`Visible 600 to 700 (13 J/cm2) Single rx
`
`Blue 417 x 6 min 1x/wk x 2 weeks
`
`ALA 20% occluded
`x 3 hours
`None
`
`Red Diode Laser 635, (15 J/cm2) 1x/wk
`x 3 weeks
`Blue 420 ⴞ 20 2x/wk x 4 weeks (40 J/
`cm2/rx cumulative dose 320 J/cm2)
`
`Blue 417 to 420 ⴛ 3 to 7 min, then 1
`pass combined bi-polar
`radiofrequency/IPL (18 to 25 J/cm2,
`18 to 20 J/cm2 RF) 2 to 4 rx 2 weeks
`apart or 2 cycles of salicylic acid peel
`at week 1 w/PDT at week 2
`Blue 417 16 min, 40 s 2x/wk x 4 weeks
`
`Blue 409 to 419, (40 mW/cm2) 10- to
`20-min exposures 2x/wk x 4 weeks
`
`Pollock 200478
`
`10 (Truncal Acne)
`
`Tzung 200479
`
`Taub 200480
`
`31 (1/2 face
`study w/self
`control)
`18
`
`ALA 20% soln X
`15 to 30 min
`
`Gold 200581
`
`Morton 200582
`
`25
`
`30
`
`None
`
`None
`
`

`

`Photodynamic therapy in dermatology
`
`57
`
`Patient No.
`8 (½ face study
`w/self control)
`
`Photosensitizer
`ALA occluded x 4
`hours
`
`Light Source (nm)
`Red 630 ⴞ 30, (18 J/cm2) Single rx
`
`IPL w/560 nm cutoff filter, (26 J/cm2) 2
`rx spaced 2 weeks apart
`
`Results
`27.6%, 37.9%, and 41.9% reduction in inflammatory
`lesions at 1, 3 and 6 months. 8.0%, 14.7% and 15.4%
`reduction seen in control
`Global improvement seen by week 2, by week 4 greater
`improvement noted w/ALA lasting up to week 8
`
`IPL with 560 to 590 cutoff filter, (25 to
`30 J/cm2), 3 rx at 3- to 4-week
`intervals
`Red, 9 min (37 J/cm2) 2 rx, 2 weeks
`apart
`
`87.7% decrease in lesions w/ALA at 12 weeks, 66.8%
`decrease w/IPL alone at 12 weeks, side effects
`included mild edema and crusting
`29% increase in comedonal lesions, 68% decrease in
`inflammatory lesions at week 12
`
`Table 2 Continued
`Reference
`Hong 200583
`
`Santos 200584
`
`Rojanamatin 200685
`
`Wiegell 200686
`
`Wiegell 200615
`
`Horfelt 200687
`
`Gold 200788
`
`Yeung 200789
`
`ALAs to ½ face x 3
`hours, light rx to
`both sides
`ALA under
`occlusion x 30
`min to ½ face
`MAL under
`occlusion x 3
`hour
`ALA or MAL under
`occlusion x 3 hrs
`
`MAL under
`occlusion x 3
`hours, split face
`study
`
`13
`
`14
`
`21
`
`15
`
`30
`
`19
`
`30
`
`59% decrease in inflammatory lesions at week 12, no
`difference between groups, side effects were greater
`w/ALA and included erythema, acne flare, and peeling
`63% vs 28% reduction in inflammatory lesions of
`treatment group vs control at 6 weeks, 54 vs 20% at
`week 12, no difference between groups w/comedonal
`lesions, side effects included pain, redness and
`swelling
`54.5% decrease inflammatory lesions, 37.5% decrease
`comedonal lesions
`No difference in inflammatory lesions between PDT, IPL
`or control at 4 & 12 weeks, 38% (PDT) and 43% (IPL)
`improvement in comedonal lesions at 12 weeks, 25%
`of PDT subjects withdrew due to side effects
`ALA, 20% 5-aminolevulinic acid oil in water emulsion; ALAs, 20% 5-aminlevulinic acid solution: IPL, Intense pulsed light; MAL, methyl aminolevulinate 160 mg/g; rx, treatment, ELOS.
`
`Red, (37 J/cm2) single rx
`
`Red light 635, (37 J/cm2) 2 rx, 2 weeks
`apart
`
`ALAs x 15 to 30
`min
`MAL 16% ⴛ 30 min
`
`AFT pulsed light 420 to 950 4 rx, 2
`weeks apart
`IPL 530 to 750 4 rx, 3 weeks apart
`
`

`

`58
`
`M.A. MacCormack
`
`Infectious Disease
`Leishmania
`A number of reports have described efficacy in the treatment
`of cutaneous leishmaniasis by PDT.95-97 The largest of these
`involved 60 patients with Old-World cutaneous leishmania-
`sis who were treated for 4 weeks with either weekly PDT
`(10% ALA applied under occlusion for 4 hours followed by
`red light irradiation 633 nm, 100J/cm2), twice daily topical
`paromomycin or placebo. Patients were followed for 2
`months.95 Resolution of lesions was 93.5% PDT, 41.2% paro-
`momycin, and 13.3% placebo. Interestingly, Leishmania are
`deficient in seven of the eight enzymes required for heme
`synthesis and are unable to convert ALA to PpIX. Thus, the
`parasiticidal effect noted is attributed to host factors such as
`vascular damage and effects on macrophages.98
`
`Dermatophytes
`On the basis of successful in vitro data,99 Calzavara-Pinton
`and coworkers treated 9 patients with interdigital mycosis
`using 20% ALA in Eucerin cream applied to one foot for 4
`hours followed by red light (75J/cm2). Treatments were re-
`peated weekly until lesions resolved for up to 4 weeks. Over-
`all response was 66%, however, 4 patients recurred after 4
`weeks.100
`
`Warts/Molluscum Contagiosum
`Early studies evaluating the use of PDT for the treatment of
`warts were disappointing, likely due to poor penetration of
`both the photosensitizing agent and light source.9,101 Later
`studies incorporated simple interventions such as paring hy-
`perkeratotic skin and use of keratolytics, efficacy subse-
`quently improved.102,103 Schroeter and coworkers treated 48
`plantar warts pared to the papillary dermis with 20% ALA
`cream applied for 4 to 8 hours followed by blue light activa-
`tion. Treatments were performed every 2 to 4 weeks with an
`average of 2.3 treatments. Complete response was seen in
`88%.104 Stender and coworkers studied 232 foot and hand
`warts that were pared and treated with a keratolytic and then
`assigned to placebo or 20% ALA followed by red light (70
`J/cm2). Complete response was 16% versus 17%, 50% versus
`35%, and 56 versus 42% at weeks 7, 14, and 18 for ALA-PDT
`and placebo respectively.102 Positive response utilizing 20%
`ALA solution applied for 14 to 24 hours followed by illumi-
`nation with blue light (417 nm, 10 J/cm2) with up to 5 treat-
`ments performed at 2-week intervals has also been described
`in the treatment molluscum contagiosum.105,106
`
`Cutaneous T-Cell Lymphoma/
`Extramammary Paget’s Disease
`Nonmelanotic skin cancer is not the only form of malig-
`nancy that responds to PDT. Numerous reports highlight
`the efficacy of PDT in the treatment of cutaneous T-cell
`lymphoma.107-109 Complete remission with no recurrence
`over 14 to 18 months was obtained in 4 patients with therapy-
`resistant stage IA-IIB lesions with 2 to 7 cycles of 20% ALA
`
`cream applied for 6 hours followed by activation with visible
`light (580-740 nm).107 Good results have also been described
`using MAL110 and in the treatment of Woringer-Kolopp.111
`As would be expected due to limited penetration of both
`photosensitizing agent and activating light source, tumor
`stage cutaneous T-cell lymphoma appears to be somewhat
`more resistant to treatment.112 Efficacy in the treatment of
`extra-mammary Paget’s disease ranges from 50% to 100%
`initial response.113-116 Recurrence tends to be high (38-50%)
`but despite this is comparable with that observed with surgi-
`cal treatment (31-61%).113
`
`Psoriasis
`Although PDT has been shown to induce T-cell apoptosis in
`psoriatic plaques,117 clinically efficacy leaves much to be de-
`sired in the treatment of plaque psoriasis. Despite the use of
`multiple different treatment protocols, almost all investiga-
`tors have seen low response rates,118 high rates of relapse
`(100% within 2 weeks),119 and numerous side effects such as
`pain120 and koebnerization.121 One potential exception ap-
`pears to be palmoplantar psoriasis (PPP). Two separate case
`reports describe success in the treat of PPP using either top-
`ically applied hematoporphyrin derivative and visible light122
`or 20% ALA followed by 632 nm diode laser activation.123
`These findings were echoed by a slighter larger case series in
`2007 in which 3 cases of refractory PPP were treated with
`20% ALA with red light activation (15 J/cm2). Mild-to-mod-
`erate improvement was appreciated in all subjects.124
`
`Photorejuvenation/Cosmesis
`While using ALA-PDT in the treatment of patients with ac-
`tinic damage and skin cancer, many investigators noted an
`incidental improvement in overall cosmesis.59 Goldman and
`coworkers treated 32 patients with 20% ALA solution ap-
`plied for 15 to 20 hours followed by blue light and found that
`72% experienced an improvement in skin texture.125 Other
`investigators describe decreased sallowness, decreased fine
`skin wrinkling, and improvement in mottled hyperpigmen-
`tation after short contact (1-3 hours) ALA with blue light
`exposure.11 Most of the work focused on cosmesis, however,
`has used IPL as the activating light source. A split face study
`by Alster and coworkers compared 2 treatments 1 month
`apart of either IPL alone or IPL ⫹ ALA. Greater improvement
`was noted in the IPL ⫹ ALA cohort; however, these patients
`also had greater side effects, such as mild edema, erythema,
`and peeling.126 A similar study by Dover and coworkers
`treated 20 patients with 3 treatments 3 weeks apart. Com-
`bined ALA-IPL had better results than IPL alone with regards
`to improvement in photoaging (80% versus 50%), mottled
`pigmentation (95% versus 65%), and fine lines (55% versus
`20%). Side effects were equal in both groups.127 Improved
`response to ALA-IPL versus. IPL was further corroborated by
`Gold and coworkers.128 Guidelines regarding settings for IPL
`devices used in conjunction with ALA can be found in a 2007
`review article by Nootheti and Goldman.129
`
`

`

`Photodynamic therapy in dermatology
`
`59
`
`Miscellaneous Case Reports
`A number of individual case reports describe success using
`PDT to treat nephrogenic fibrosing dermopathy,130 granu-
`loma annulare,131 disseminated superficial actinic porokera-
`tosis,132 necrobiosis lipoidica diabeticorum,133 lymphadeno-
`sis benigna cuitis,134 mycobacterium marinum,135 both
`success,136 and failure137 in the treatment of Darier’s disease
`and both success138 and failure in the treatment of hidrade-
`nitis suppurativa.139
`
`Summary
`Photodynamic therapy is a safe, noninvasive therapeutic mo-
`dality that allows for the treatment of broad areas with gen-
`erally excellent cosmesis. Current use centers primarily on
`the treatment of actinic damage and early nonmelanotic skin
`cancers, yet recent work supports its use in the treatment
`numerous other conditions ranging from cosmetic interven-
`tions to infectious processes. As further advances overcome
`current limitations, such as inadequate penetration of both
`light source and photosensitizing agent, the use of PDT in
`dermatology will likely increase.
`
`References
`1. Kennedy JC, Pottier RH: Endogenous protoporphyrin IX, a clinically
`useful photosensitizer for photodynamic therapy. J Photochem Pho-
`tobiol B 14:275-292, 1992
`2. Ackroyd R, Kelty C, Brown N, et al: The history of photodetection and
`photodynamic therapy. Photochem Photobiol 74:656-669, 2001
`3. Daniell MD, Hill JS: A history of photodynamic therapy. Aust N Z
`J Surg 61:340-348, 1991
`4. Kato H: [History of photodynamic therapy—past, present and future].
`Gan To Kagaku Ryoho 23:8-15, 1996
`5. Taub AF: Photodynamic therapy in dermatology: History and hori-
`zons. J Drugs Dermatol 3:S8-25, 2004 (suppl 1)
`6. Hilf R: Mitochondria are targets of photodynamic therapy. J Bioenerg
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`7. Lam M, Oleinick NL, Nieminen AL: Photodynamic therapy-induced
`apoptosis in epidermoid carcinoma cells. Reactive oxygen species and
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`47379-47386, 2001
`8. Korbelik M: PDT-associated host response and its role in the therapy
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`9. Kennedy JC, Pottier RH, Pross DC: Photodynamic therapy with en-
`dogenous protoporphyrin IX: Basic principles and present clinical
`experience. J Photochem Photobiol B 6:143-148, 1990
`Jeffes EW, McCullough JL, Weinstein GD, et al: Photodynamic ther-
`apy of actinic keratoses with topical aminolevulinic acid hydrochlo-
`ride and fluorescent blue light. J Am Acad Dermatol 45:96-104, 2001
`11. Touma D, Yaar M, Whitehead S, et al: A trial of