Aminolevulinic Acid: Actinic
`Keratosis and Photorejuvenation
`
`Melanie Palm and Mitchel P. Goldman
`
`2
`
`Abstract
`ALA-PDT is a safe and effective treatment for nonhyperkeratotic lesions.
`Although FDA-approved for use with a blue light source, other laser and
`light sources have demonstrated promise in the treatment of actinic kera-
`tosis during PDT. Shorter incubation times maintain AK clearance rates
`but decrease the occurrence of phototoxic adverse events. With careful
`patient selection, ALA-PDT allows selective field treatment of precancer-
`ous skin lesions with improvement in overall photodamage. Patient satis-
`faction is high and cosmetic results can be excellent.
`
`Aminolevulinic acid (ALA) was the first photo-
`sensitizer prodrug to be FDA-approved for use in
`topical photodynamic therapy (PDT). Since its
`approval over a decade ago, many aspects of
`ALA-PDT have been examined. Studies investi-
`gating the treatment of nonhyperkeratotic actinic
`keratosis (AK) with ALA-PDT have led to
`advances in treatment. Incubation times of ALA
`have decreased, multiple light sources have been
`used to elicit the reaction, and cosmetic benefits of
`treatment have been discovered. In the discussion
`that follows, background on ALA-PDT is pro-
`vided. In addition, clinical studies regarding the
`treatment of AKs and photorejuvenation are sum-
`marized. Finally, a practical guide for treatment is
`provided for the reader to optimize treatment
`while avoiding common pitfalls of treatment.
`
`M. Palm ()
`Surfside Dermatology, Encinitas, CA, USA
`e-mail: melanie.palm@gmail.com
`
`Mechanism of PDT
`
`PDT Mechanism of Action
`
`PDT involves the activation of a photosensitizer
`by light in the presence of an oxygen-rich envi-
`ronment. Topical PDT involves the application of
`ALA or its methylated derivative (MAL) to the
`skin for varying periods of time. This leads to the
`conversion of ALA to protoporphyrin IX (PpIX),
`an endogenous photactivating agent. PpIX accu-
`mulates in rapidly proliferating cells of premalig-
`nant and malignant lesions [1], as well as in
`melanin, blood vessels, and sebaceous glands
`[2]. Upon activation by a light source and in the
`presence of oxygen, the sensitizer (PpIX) is oxi-
`dized, a process called “photobleaching” [3].
`During this process, free radical oxygen singlets
`are generated, leading to selective destruction of
`tumor cells by apoptosis without collateral dam-
`age to surrounding tissues [4, 5]. Selective
`destruction of malignant cells is due in part to
`their reduced ferrochetalase activity, leading to
`
`M.H. Gold (ed.), Photodynamic Therapy in Dermatology,
`DOI 10.1007/978-1-4419-1298-5_2, © Springer Science+Business Media, LLC 2011
`
`5
`
`

`

`Aminolevulinic Acid: Actinic
`Keratosis and Photorejuvenation
`
`Melanie Palm and Mitchel P. Goldman
`
`2
`
`Abstract
`ALA-PDT is a safe and effective treatment for nonhyperkeratotic lesions.
`Although FDA-approved for use with a blue light source, other laser and
`light sources have demonstrated promise in the treatment of actinic kera-
`tosis during PDT. Shorter incubation times maintain AK clearance rates
`but decrease the occurrence of phototoxic adverse events. With careful
`patient selection, ALA-PDT allows selective field treatment of precancer-
`ous skin lesions with improvement in overall photodamage. Patient satis-
`faction is high and cosmetic results can be excellent.
`
`Aminolevulinic acid (ALA) was the first photo-
`sensitizer prodrug to be FDA-approved for use in
`topical photodynamic therapy (PDT). Since its
`approval over a decade ago, many aspects of
`ALA-PDT have been examined. Studies investi-
`gating the treatment of nonhyperkeratotic actinic
`keratosis (AK) with ALA-PDT have led to
`advances in treatment. Incubation times of ALA
`have decreased, multiple light sources have been
`used to elicit the reaction, and cosmetic benefits of
`treatment have been discovered. In the discussion
`that follows, background on ALA-PDT is pro-
`vided. In addition, clinical studies regarding the
`treatment of AKs and photorejuvenation are sum-
`marized. Finally, a practical guide for treatment is
`provided for the reader to optimize treatment
`while avoiding common pitfalls of treatment.
`
`M. Palm ()
`Surfside Dermatology, Encinitas, CA, USA
`e-mail: melanie.palm@gmail.com
`
`Mechanism of PDT
`
`PDT Mechanism of Action
`
`PDT involves the activation of a photosensitizer
`by light in the presence of an oxygen-rich envi-
`ronment. Topical PDT involves the application of
`ALA or its methylated derivative (MAL) to the
`skin for varying periods of time. This leads to the
`conversion of ALA to protoporphyrin IX (PpIX),
`an endogenous photactivating agent. PpIX accu-
`mulates in rapidly proliferating cells of premalig-
`nant and malignant lesions [1], as well as in
`melanin, blood vessels, and sebaceous glands
`[2]. Upon activation by a light source and in the
`presence of oxygen, the sensitizer (PpIX) is oxi-
`dized, a process called “photobleaching” [3].
`During this process, free radical oxygen singlets
`are generated, leading to selective destruction of
`tumor cells by apoptosis without collateral dam-
`age to surrounding tissues [4, 5]. Selective
`destruction of malignant cells is due in part to
`their reduced ferrochetalase activity, leading to
`
`M.H. Gold (ed.), Photodynamic Therapy in Dermatology,
`DOI 10.1007/978-1-4419-1298-5_2, © Springer Science+Business Media, LLC 2011
`
`5
`
`

`

`6
`
`M. Palm and M.P. Goldman
`
`excessive accumulation of intracellular PpIX [6].
`Recent in vitro research suggests that any remain-
`ing malignant cells following PDT have reduced
`survival [7]. A detailed explanation of the mecha-
`nism of action in PDT is found in Chap. 1.
`
`ALA
`
`d-5-ALA is a hydrophilic, low molecular weight
`molecule within the heme biosynthesis pathway
`[1, 8]. ALA is considered a prodrug [9]. In vivo,
`it is converted to PpIX, a photosensitizer in the
`PDT reaction. In the United States, ALA is avail-
`able as a 20% topical solution manufactured
`under the name Levulan Kerastick (DUSA
`Pharmaceuticals, Inc., Wilmington, MA). FDA-
`approved since 1999, Levulan is used for the
`treatment of nonhyperkeratotic AKs in conjunc-
`tion with a blue light source, such as the Blu-U
`(DUSA, Wilmington, MA) [10]. It is supplied as
`a cardboard tube housing two sealed glass
`ampules, one containing 354 mg of d-ALA
`hydrochloride powder and the other 1.5 mL of
`solvent [6]. The separate components are mixed
`within the cardboard sleeve just prior to use.
`Esters of ALA are lipophilic derivatives of the
`parent molecule. Their chemical structure pro-
`vides increased lipophilicity, allowing superior
`penetration through cellular lipid bilayers com-
`pared to ALA [2, 11]. MAL may offer better
`tumor selectivity [11–14] and less pain [14, 15]
`during PDT with less patient discomfort [15]
`compared to ALA.
`
`Light Irradiation
`
`No standardized guidelines for the “optimal irradi-
`ance, wavelength and total dose characteristics for
`PDT” exist according to the British Dermatology
`group and the American Society of Photodynamic
`Therapy Board [9, 16, 17]. However, certain laser
`and light sources are predictably chosen for PDT
`activation. Their wavelengths correspond closely
`with the four absorption peaks along the porphyrin
`curve. The Soret band (400–410 nm), with a
`
`maximal absorption at 405–409 nm, is the highest
`peak along this curve for photoactivating PpIX.
`Smaller peaks designated as the “Q bands” exist
`at approximately 505–510, 540–545, 580–584,
`and 630–635 nm [1, 2, 8]. There are advantages
`and disadvantages to exploiting the wavebands in
`either the Soret or Q bands for PDT. The Soret
`band peak is 10 to 20-fold larger than the Q
`bands, and blue light sources are often used to
`activate PpIX within this portion of the porphyrin
`curve, targeting lesions up to 2 mm in depth [14].
`Longer wavelengths found within the Q bands
`produce a red light that penetrates more deeply
`(5 mm into the skin) but necessitates higher
`energy requirements [1, 8].
`
`Light Sources
`
`Light sources used in PDT can be categorized in
`a variety of ways, including incoherent versus
`coherent sources, or by color (and wavelengths)
`emitted. Incoherent light is emitted as noncolli-
`mated light and is provided through broadband
`lamps, light emitting diodes (LEDs), and intense
`pulsed light (IPL) systems. Noncoherent light
`sources are easy to use, affordable, easily
`obtained, and portable due to their compact size
`[18]. The earliest uses in PDT were filtered slide
`projectors that emitted white light [1]. Metal hal-
`ogen lamps such as the Curelight (Photocure,
`Oslo, Norway, 570–680 nm) are often employed
`in PDT as they provide an effective light source
`in a time, power, and cost-effective manner [1,
`19]. In Europe, the PDT 1200 lamp (Waldmann
`Medizintechnik, VS-Schwennigen, Germany)
`gained in popularity, providing a unit with high
`power density emitting a circular field of light
`radiation from 600 to 800 nm [12, 19]. Short arc,
`tunable xenon lamps have also been used, emit-
`ting light radiation from 400 to 1,200 nm [12].
`The only widely available fluorescent lamp used
`in conjunction with PDT is the Blu-U (DUSA,
`Wilmington, MA) with a peak emittance at
`417 ± 5 nm. LEDs provide a narrower spectrum
`of light irradiation, usually in a 20–50 nm
`bandwidth via a compact, solid, but powerful
`
`

`

`2 Aminolevulinic Acid: Actinic Keratosis and Photorejuvenation
`
`7
`
`semiconductor [1, 20]. LEDs are simple to oper-
`ate and are typically small in size, emitting light
`from the UV to IR portion of the electromagnetic
`spectrum [20]. However, the diminutive size of
`most LED panels necessitates multiple rounds of
`light illumination to treat larger areas. IPL is yet
`another source of incoherent light, emitting a
`radiation spectrum from approximately 500 to
`1,200 nm [20]. Cutoff filters allow customization
`of the delivered wavelengths. This light source is
`particularly useful in photorejuvenation, target-
`ing pigment, blood vessels, and even collagen.
`Lasers provide precise doses of light radia-
`tion. As collimated light sources, lasers deliver
`energy to target tissues at specific wavelengths
`chosen to mimic absorption peaks along the por-
`phyrin curve. Lasers used in PDT include the tun-
`able argon dye
`laser
`(blue-green
`light,
`450–530 nm) [12], the copper vapor laser-pumped
`dye laser (510–578 nm), long-pulse pulsed dye
`lasers (PDL) (585–595 nm), the Nd:YAG KTP
`dye laser (532 nm), the gold vapor laser (628 nm),
`and solid-state diode lasers (630 nm) [19].
`Although laser sources allow the physician to
`delivery light with exact specifications in terms
`of wavelength and fluence, the fluence rate should
`be kept in the range of 150–200 mW/cm2 to avoid
`hyperthermic effects on tissue [1, 14]. In fact,
`there is evidence to support that cumulative light
`dose of greater than 40 J/cm2 can deplete all
`available oxygen sources during the oxidation
`reaction, making higher doses of energy during
`PDT unnecessary [3].
`
`Clinical Applications
`
`Actinic Keratoses
`
`Background and Epidemiology
`Actinic keratoses (AK) are a premalignant skin
`condition, comprising the third most common
`reason and 14% of all dermatology office visits
`[21, 22]. Approximately 4 million Americans
`are diagnosed with AKs annually [23], and
`according to one Australian study, 60% of
`Caucasian Australians aged 40 or older develop
`
`this condition [24]. The prevalence of AKs
`within the US population ranges from 11 to 26%
`with the highest incidence in southern regions
`and older Caucasian patients [25].
`The concern for untreated AKs is their rate of
`transformation to cutaneous squamous cell carci-
`noma (SCC). A small percentage of SCC metas-
`tasizes [26], and this is more likely in higher risk
`areas, such as mucous membranes (e.g., lips)
`[27]. The reported conversion rate of AK to SCC
`varies widely, estimated as 0.025–16% per lesion
`per year [28–32]. AKs may be considered an in situ
`SCC [33, 34], with AK resting on the precancer-
`ous end of a spectrum that leads toward invasive
`SCC. It has been suggested that the AK/SCC
`continuum be graded as “cutaneous intraepithe-
`lial neoplasia,” in a manner analogous to cervical
`malignancy. Further histopathologic evidence
`supports the link between AKs and SCC. Both
`lesions express tumor markers including the
`tumor suppressor gene p53 [35] and over 90% of
`biopsied SCCs have adjacent AKs within the
`examined histopathologic field [36].
`
`Clinical Presentation and Diagnosis
`AKs typically appear as 1–3 mm slightly scaly
`plaques on an erythematous base, often on a
`background of solar damage. They are often
`detected more easily through palpation than
`visual detection [37], due to their hyperkeratotic
`nature. The surrounding skin often shows signs
`of moderate to severe photodamage, including
`dyspigmentation, telangiectasias, and sallow col-
`oration due to solar elastosis (Fig. 2.1). Individual
`AK lesions may converge, creating larger con-
`tiguous lesions. Most AKs are subclincial and not
`readily apparent to visual or palpable examina-
`tion. The evidence for subclinical AKs is their
`fluorescence when exposed to ALA + Wood’s
`lamp or a specialized CCD camera [38].
`Although often asymptomatic, AKs may have
`accompanying burning, pruritus, tenderness, or
`bleeding [22]. Several variants of AK exist,
`including nonhyperkeratotic (thin), hyperkera-
`totic, atrophic, lichenoid, verrucous, horn-like
`(cutaneous horn), and pigmented variants [25].
`AKs on the lip, most often occurring on the lower
`
`

`

`8
`
`M. Palm and M.P. Goldman
`
`Fig. 2.1 Frontal scalp of a 71-year-old white male dem-
`onstrating moderate to severe photodamage. Numerous
`actinic keratoses characterized by erythematous scaly
`slightly elevated plaques are visible on a background of
`extensive solar lentigines
`
`lip, are designated as actinic cheilitis [27].
`As AKs often result from a long history of UV
`exposure, the lesions usually arise in heavily sun-
`exposed areas including the scalp, face, ears, lips,
`chest, dorsal hands, and extensor forearms [39].
`Risk factors for AKs include fair skin (Fitzpatrick
`skin type I–III), history of extensive, cumulative
`sun exposure, increasing age, elderly males (due
`to UV exposure), history or arsenic exposure, and
`immunosuppression [21, 22].
`
`Histopathology
`Histopathologic examination of actinic keratoses
`is characterized by atypical keratinocytes and
`architectural disorder [22]. Early lesions demon-
`strate focal keratinocyte atypia originating at
`the basal layer of the epidermis and extending
`variably upward within the epidermis [40].
`Hyperchromatic and pleomorphic nuclei and
`nuclear crowding characterize the cellular find-
`ings while architectural disorder is comprised of
`alternating ortho- and hyperkeratosis, hypogran-
`ulosis, and focal areas of downward budding in
`the basal layer of the epidermis [22, 25]. Solar
`elastosis is invariably present. Well-developed
`lesions may have apoptotic cells, mitotic figures,
`involvement of adnexal structures, lichenoid infil-
`trates, and a focal tendency toward full-thickness
`involvement (Fig. 2.2). Full-thickness atypia
`indicates transformation into SCC-in situ [25].
`
`Fig. 2.2 ( a) Histopathologic section of actinic keratosis
`stained with hematoxylin and eosin at 20× magnification.
`Lesion is characterized by alternating ortho- and hyper-
`keratosis with nuclear atypia and architectural disorder.
`Keratinocyte atypia approaches full-thickness in middle
`area of lesion. Note the gray, fragmented nature of the
`papillary dermis representing extensive solar elastosis.
`(b) Actinic keratosis, lichenoid variant. A brisk lympo-
`cytic infiltrate in the papillary dermis accompanies cyto-
`logic atypia of epidermal keratinocytes and marked
`architectural disorder. Numerous apoptotic cells are visi-
`ble within the epidermis (Courtesy of Wenhua Liu, MD,
`Consolidated Pathology Consultants, Inc., Libertyville, IL)
`
`Treatment Rationale
`Treatment Options for AKs. Given the premalig-
`nant potential of AKs, and the metastatic potential
`of SCC, early treatment is paramount to preventing
`disease progression. Treatment options for AKs
`depend on a variety of factors including severity of
`involvement, duration or persistence of lesions,
`patient tolerability or desire for cosmesis, afford-
`ability/insurance coverage, and physician comfort
`with available treatment modalities [22, 32].
`
`

`

`2 Aminolevulinic Acid: Actinic Keratosis and Photorejuvenation
`
`9
`
`Although AKs can reliably be diagnosed by clinical
`examination alone [41], a low threshold for biopsy
`should be exercised on atypical lesions, or lesions
`not responsive to prior treatment.
`While singular or few
`lesions may be
`approached with local, surgical treatment such as
`cryotherapy, curettage, excision, or dermabra-
`sion, field treatment may be more appropriate
`when numerous lesions are identified. In addi-
`tion, field therapy will treat subclinical AKs.
`Chemical peels, laser resurfacing, 5-fluorouracil
`(5-FU), topical diclofenac, topical retinoids, and
`topical immunomodulators (imiquimod) are all
`reasonable treatment options in addition to PDT.
`A comparison of PDT to other field treatment
`options for AKs yields comparable clearance
`rates [42, 43]. In fact, a comparison of 100%
`clearance rates from phase III clinical trials
`reported complete AK clearance with ALA-PDT
`of 72%, comparable to 5-FU (72%), and superior
`to imiquimod (49%) and diclofenac (48%) [23].
`A direct comparison study by Kurwa et al. [44]
`found comparable lesion area reduction rates
`between ALA-PDT (73%) and 5-FU (70%).
`
`Advantages/Disadvantages of ALA-PDT
`for AKs
`Clearance rates of AKs following PDT has ranged
`from 68 to 98% [45, 46]. Assuming near equiva-
`lent or even superior clearance rates of PDT com-
`pared to other field treatment options, PDT has
`several advantages in the treatment of AKs.
`Improvement of photodamage, superior cosme-
`sis, and better patient satisfaction were docu-
`mented in two studies by Szeimies et al. [43] and
`Goldman and Atkin [46]. Other procedures used
`for the clearance of AKs such as cryotherapy or
`chemical peels can result in hypopigmentation or
`even scarring [43, 47]. PDT, perhaps surprisingly
`to some, is a cost-effective means of treating AKs.
`Gold found ALA-PDT with a blue light source to
`be the least expensive treatment option for AKs
`compared to 5-FU, imiquimod, and diclofenac. In
`fact, ALA-PDT was approximately one-half the
`cost of a similar course of imiquimod for field
`AK treatment [23]. Additionally, PDT accom-
`plished field treatment of precancerous lesions
`including subclinical ones [47].
`
`Disadvantages of PDT are largely related to
`minor and expected adverse events following the
`procedure. Minor pain and erythema may occur
`during or following the procedure. Mild crusting
`and edema may occur, lasting up to 1 week.
`However, other treatment modalities for AKs
`have similar if not longer recovery periods. There
`are financial costs associated with the procedure.
`If PDT is performed for AK treatment and photo-
`rejuvenation, there is an associated out-of-pocket
`cost to the patient. The physician must also make
`an initial investment in the laser and light devices,
`although many of the light sources have multiple
`applications beyond PDT.
`
`Treatment Results of ALA-PDT for AKs
`Kennedy et al. [48], in 1990, was the first to
`exploit the use of topical 5-ALA in the treatment
`of nonmelanoma skin cancers. Using a 20% ALA
`compound and a filtered slide projector for a light
`source, a complete response rate of 90% was
`achieved in patients with AKs. Since this initial
`study, a variety of light sources have been inves-
`tigated for use in PDT for the treatment of AKs.
`As the PDT reaction is activated from an emis-
`sion spectra ranging from 400 to 800 nm [49], we
`have organized clinical studies according to the
`light source used. Table 2.1 provides a summary
`of peer-reviewed articles on the use of ALA-PDT
`in AK treatment.
`
`Violet Light. A relatively recent study published
`by Dijkstra et al. [49] in 2001 investigated the use
`of violet light in ALA-PDT. The use of this emis-
`sion spectrum was based on the premise that
` violet light was ten times more effective than
`red light in photosensitization with ALA [49].
`A study population of 38 patients with varying
`skin conditions including BCC (2 patients with
`Gorlin–Goltz syndrome), Bowen’s disease, and
`actinic keratoses were treated. A 20% ALA gel
`was applied to lesions for 8 hours under occlu-
`sion. Photoactivation followed using a lamp with
`a cold glass filter, emitting a spectrum of light
`between 400 and 450 nm. The sample size of AKs
`in this study was extremely small (n = 4), making
`conclusions about violet light in ALA-PDT diffi-
`cult. A clearance rate for the four AKs treated
`
`

`

`10
`
`M. Palm and M.P. Goldman
`
`4
`
`3–12
`
`85% CR
`
`50% CR
`
`12
`
`2
`
`1
`
`6
`
`15
`
`36
`
`1
`
`3–20
`12
`
`24–36
`3–12
`18
`(months)
`Follow-up
`
`extremities
`neck; 56% CR
`82% CR face and
`(5-FU)
`to 5-fluorouracil
`reduction; comparable
`73% Lesion area
`79% CR (PDL)
`84% CR (red light)
`and extremities
`scalp; 45% CR trunk
`91% CR face and
`
`green and red light
`100% CR for both
`
`71% CR
`
`71% CR head
`81% CR
`100% CR
`
`100% CR
`100% CR
`90% CR
`Response rate
`
`Blue light (417)
`(400–450)
`Violet lamp
`(630)
`excimer dye laser
`range 600–700),
`Red lamp (peak 630,
`
`(580–740)
`Metal halide lamp
`740) or PDL (585)
`Red light lamp (580–
`
`(630)
`Argon dye laser
`(570–750)
`Waldmann lamp
`(543–548) vs. red
`Green lamp
`515, 530, 570, 610
`with cutoff filters at
`projector (300–800)
`Halogen slide
`(580–740)
`Waldmann red lamp
`Halogen (570–690)
`Xenon (630)
`
`(630)
`Argon dye laser
`Tungsten, unfiltered
`Tungsten (>600)
`length in nm)
`Light source (wave-
`
`70 (36)
`
`14–18
`
`Face, scalp
`
`4
`
`8, Occluded
`
`Unspecified
`
`20% Solution
`sessions
`20% Gel, two
`
`Jeffes et al. [42]
`
`Dijkstra et al. [49]
`
`53 (10)
`
`4, Occluded
`
`extremities
`Face, neck,
`
`or more sessions
`20% Emulsion, two
`
`Itoh et al. [58]
`
`(14)
`
`4, Occluded
`
`Hands
`
`20% Emulsion
`
`Kurwa et al. [44]
`
`200 (24)
`
`6, Occluded
`
`Scalp, face
`
`20% Emulsion
`
`Karrer et al. [57]
`
`240 (40)
`
`3, Occluded
`
`extremities
`Face, scalp, trunk,
`
`0–30% Emulsion
`
`Jeffes et al. [56]
`
`(6)
`
`6, Occluded
`
`Face and scalp
`
`10% Ointment
`
`Fritsch et al. [54]
`
`251 (28)
`
`4, Occluded
`
`hands
`forearms, dorsal
`Head, neck,
`
`20% Emulsion
`
`[61]
`Fink-Puches et al.
`
`36 (10)
`43 (9)
`
`4
`
`6, Occluded
`20, Occluded
`
`4
`
`Head, hands, arms
`Not specified
`Face and scalp
`
`10% Emulsion
`20% Emulsion
`20% Emulsion
`
`Szeimies et al. [87]
`Fijan et al. [86]
`Morton et al. [85]
`
`Bowen’s)
`AKs, BCCs, SCCs,
`85 patients with
`50 (From pool of
`
`9
`
`10
`(# patients)
`# Lesions treated
`
`6–8
`4–8
`3–6
`period (hours)
`Incubation
`
`Face
`Face and scalp
`Not specified
`Location of AKs
`
`20% Cream
`20% Emulsion
`20% Emulsion
`ALA preparation
`
`et al. [1]
`Calzavara-Pinton
`Wolf et al. [5]
`Kennedy et al. [48]
`References
`
`Table 2.1 Published clinical studies on ALA-PDT for AKs
`
`

`

`2 Aminolevulinic Acid: Actinic Keratosis and Photorejuvenation
`
`11
`
`12
`
`12
`
`3
`
`12
`
`3
`
`5
`
`12
`
`1
`
`3–6
`
`11
`
`6
`
`6
`
`3
`
`8
`
`lesions >10 mm diameter
`<10 mm; 70% CR in
`100% CR in lesions
`
`86% two sessions
`72–76% CR one session;
`50%
`
`tion therapy
`90% CR with combina-
`87–94% CR
`83% CR two sessions
`91% CR one session;
`at 48 weeks
`94% CR at 4 weeks; 72%
`60% CR for PDL
`80% CR for blue light;
`pigmentation
`improved skin texture,
`94% CR of AKs;
`
`91% CR
`
`(630)
`Excimer dye laser
`
`(30)
`
`4, Occluded
`
`Face
`
`Blue (417)
`IPL (555–950)
`
`968 (110)
`12 (7)
`
`14–18
`4, Occluded
`
`Face, scalp
`Face
`
`IPL (560–1,200)
`Blue lamp (417)
`
`(15)
`(17)
`
`0.5–0.75
`1–3
`
`Face
`Face
`
`Blue (417)
`
`1,402 (243)
`
`14–18
`
`Face, scalp
`
`Red light (580–740)
`PDL (595)
`Blue light (417) or
`
`Blue light (417)
`laser (630)
`lamp (570–680), diode
`(590–730); Halogen
`Metal halide
`
`(35)
`
`(32)
`
`23
`
`32 (20)
`
`5, Occluded
`
`Face, scalp
`
`1
`
`Face, scalp
`
`treatment sessions)
`20% Cream (three
`sessions)
`to two treatment
`20% Solution, (one
`20% Emulsion
`days pre-PDT
`5-FU daily × 5
`20% Solution,
`20% Solution
`to two sessions
`20% Solution, one
`transplant patients
`20% Emulsion;
`two sessions
`20% Solution,
`
`Nakano et al. [17]
`
`Tschen et al. [41]
`Kim et al. [62]
`
`Gilbert [63]
`Touma et al. [6]
`[52]
`Piacquadio et al.
`
`Dragieva et al. [80]
`
`Smith et al. [55]
`
`Long-pulsed PDL (595)90–100% CR
`
`3,622 (36)
`
`91% CR two sessions
`76% CR one session;
`
`IPL (590–1,200)
`
`after second, RR of 28%
`77% CR after first, 99%
`
`(580–740)
`Waldmann red lamp
`
`38
`diagnoses)
`with mixed
`127 (88 Patients
`
`75% CR
`
`Red light (580–740)
`
`(4)
`
`4, Occluded
`
`Scalp
`
`4, Occluded
`
`Not specified
`
`20% Ointment
`unspecified, cream
`% Concentration
`
`Varma et al. [59]
`Collins [21]
`Markham and
`
`15–20
`
`incubation PDT
`Face, long-
`
`20% Solution
`
`[46]
`Goldman and Atkin
`
`4
`
`Not specified
`
`20% Ointment
`
`Clark et al. [19]
`
`occlusion
`14–18 without
`Occlusion;
`3 with
`
`trunk
`Head, extremities,
`
`20% Solution
`
`4, Occluded
`
`Face, scalp
`
`20% Emulsion
`
`Geronemus [47]
`Amenakas and
`Alexiades-
`et al. [65]
`Ruiz-Rodriguez
`
`

`

`12
`
`M. Palm and M.P. Goldman
`
`with two sessions of PDT was 50% [49]. Although
`other lesions in the study had a more favorable
`clearance rate, further studies are needed to draw
` conclusions on the usefulness of violet light in
`PDT for precancerous skin lesions.
`
`Blue Light. Perhaps the most popular emission
`spectrum used in the United States, blue light
`remains the only FDA-approved form of light for
`activating ALA (Fig. 2.3). As a result, numerous
`published studies exist on the use of blue light in
`ALA-PDT not only for the treatment of AKs, but
`also for other skin conditions responsive to this
`treatment modality. The relatively shorter wave-
`length of blue light only penetrates 1–2 mm but is
`potent in its photochemical effect, therefore blue
`light is often selected for the treatment of superficial
`lesions such as nonhyperkeratotic AK lesions [50].
`In 2001, Jeffes et al. [42] published the results
`of a multicenter, phase II study of ALA-PDT using
`blue light (417 nm). A 14- to 18-hours incubation
`
`Fig. 2.3 Noncoherent blue lamp is a common choice for
`photoactivating aminolevulinic acid (ALA) in the United
`States. The Blu-U
`(DUSA Pharmaceuticals,
`Inc.,
`Wilmington, MA) emits light at a bandwidth of approxi-
`mately 417 ± 5 nm (Courtesy of DUSA Pharmaceuticals,
`Inc., Wilmington, MA)
`
`was used on AK lesions of the face and scalp in 36
`patients. A total of 70 lesions were treated. Light
`exposure duration was 16 minutes and 40 seconds,
`now considered standard of treatment. At 8 weeks
`following a single treatment, 88% of lesions
`cleared. Due to the extended time of incubation, an
`increased rate of phototoxic-related side effects
`was observed. These adverse effects included ery-
`thema and edema. A second phase II study was
`conducted with the same protocol, this time in a
`total of 64 patients [51]. All of the patients had
`75% or more clearance of AK lesions following
`one treatment. However, 14% of patients required
`reduced power density during blue light irradiation
`due to intolerable side effects including stinging
`and burning. A final phase II study was a dose-
`ranging study of ALA solution from concentra-
`tions of 2.5–30% ALA. Clearance of AKs occurred
`in a dose-dependent manner, and a 20% concentra-
`tion was selected as the most ideal concentration
`for use in ALA-PDT with blue light [51].
`Piacquadio et al. [52] followed in 2004, pub-
`lishing the results of a phase III clinical trial. The
`same long incubation and illumination times
`were used as in the phase II trial. A total of 243
`patients with nonhyperkeratotic AKs were
`treated. Complete clearance at 12 weeks follow-
`ing one PDT session was 70%. A second treat-
`ment resulted in a complete clearance rate of
`88%. Facial lesions responded more favorably
`than scalp lesions, with complete response rates
`of 78 and 50%, respectively, at week 12 follow-
`ing treatment. In terms of patient feedback, 94%
`of patients rated their cosmetic outcome follow-
`ing PDT as good or excellent. A recurrence rate
`analysis for this treatment cohort between 8 and
`12 weeks post-treatment was 5% [51].
`Several other studies examining the use of
`blue light in ALA-PDT for the treatment of non-
`hyperkeratotic AKs followed. In 2002, Gold [53]
`reported on facial AKs treated with blue light
`PDT. The response rate was favorable with 83%
`clearance. A separate study by Goldman and
`Atkin [46] demonstrated similar results. In both
`studies, photorejunative effects on the treated
`areas of the skin were noted.
`In 2004, Touma et al. [6] reported on the effi-
`cacy of short-contact ALA-PDT. Not only did
`this allow for PDT to be conducted in a single
`
`

`

`2 Aminolevulinic Acid: Actinic Keratosis and Photorejuvenation
`
`13
`
`clinic visit rather than over 2 days, but side effects
`related to the longer 14–18 h incubations were
`reduced. In this study, 17 patients with AKs of the
`face and scalp were treated with ALA using incu-
`bation times of 1, 2, or 3 h. A clearance rate of 93,
`84, and 90% were achieved in the 1-, 2-, and
`3-hour incubation groups, respectively. Clearance
`rates were maintained through 5 months of fol-
`low-up. In addition, this was the second study
`with blue light to demonstrate a modest but sig-
`nificant improvement in photoaging.
`Work by Tschen et al. [41] confirmed earlier
`findings. This phase IV study of 101 patients with
`6–12 AKs used a 14–18 hour ALA incubation
`time. After the first PDT, a complete clearance of
`72–76% was observed, which increased to 86%
`with a second treatment.
`
`Green Light. One study by Fritsch et al. [54]
`used a green light source for the treatment of AKs
`with ALA-PDT. The focus of this study was on
`patient discomfort. Compared to a red light
`source, light irradiation with a green light source
`(543–548 nm) was less painful in the treatment of
`facial AKs during PDT.
`
`Yellow-Orange Light: PDL. Long-PDL (585–
`595 nm) (Fig. 2.4) target the chromophore oxy-
`hemoglobin, allowing selective destruction of
`blood vessels. As actinic keratoses often appear
`as erythematous scaly plaques, the inflammatory
`nature of these lesions can be targeted with
`this vascular laser. Alexiades-Amenakas and
`Geronemus [47] were the first to report on its use
`in ALA-PDT. Thirty-six patients and a total of
`3,622 lesions were treated. Location of lesions
`included the face and scalp (2,620 lesions),
`extremities (949), and trunk (53). ALA was
`applied with either a 3 hour, unoccluded incuba-
`tion versus a 14–18 hour incubation. No differ-
`ence in clearance was observed between the two
`incubation time groups. Clearance rates were
`highest for head lesions at 100%. According to
`this large cohort study, it appeared that PDL at
`subpurpuric doses allows an efficient and less
`painful means of accomplishing PDT.
`In 2003, Smith et al. [55] published a three-arm
`study on 36 patients with AKs. One arm received
`treatment with low concentration 5-FU, the other
`
`Fig. 2.4 Pulsed dye lasers (PDL) may be used as a light
`source for ALA-PDT to target individual lesions includ-
`ing AKs, sebaceous hyperplasia, and solar lentigines
`(Vbeam Perfecta [595 nm] laser image printed courtesy of
`Candela Corporation, Wayland, MA)
`
`two arms received ALA-PDT – using either a
`PDL or blue light for photoactivation. A short,
`1 hour unoccluded incubation was used. Clearance
`rates at 4 weeks follow-up were similar for 5-FU
`and ALA-PDL (79% vs. 80%). Clearance rates
`of PDT using a blue light source were lower
`(60%). Additionally, improvements in global
`photodamage, hyperpigmentation, and tactile
`roughness were observed [55].
`
`Red Light Sources. The longer wavelength of red
`light allows deeper tissue penetration. Red light is
`used frequently during PDT with MAL. Red light
`may also be used for photoactivation of PpIX dur-
`ing ALA-PDT. Several laser and light sources emit
`wavelengths in the red light spectrum, usually
` targeted around 630 nm. These include the argon
`
`

`

`14
`
`M. Palm and M.P. Goldman
`
`pumped dye laser, excimer laser, metal halide
`lamps, and red LED lamps.
`
`Red Light from Laser Sources. One of the earli-
`est studies reporting on ALA-PDT was com-
`pleted by Calzavara-Pinton et al. [1] using an
`argon pumped dye laser (630 nm). In the treat-
`ment of 50 facial AK lesions, 20% ALA cream
`was applied topically for 6–8 hours. The study’s
`patient population also included a mixed pool of
`85 total patients with diagnoses of Bowen’s dis-
`ease, SCCs, BCCs, and AKs. In terms of AK out-
`comes, a clearance rate of 100% was achieved at
`24–36 months posttreatment.
`The initial phase I clinical study for FDA-
`approval of ALA in PDT also utilized an argon
`pu