REVIEW ARTICLE
`Photodynamic Therapy: A Clinical Consensus Guide
`David M. Ozog, MD,* Ali M. Rkein, MD,† Sabrina G. Fabi, MD,‡x Michael H. Gold, MD,¶
`Mitchel P. Goldman, MD,k# Nicholas J. Lowe, MD,** George M. Martin, MD,††
`and Girish S. Munavalli, MD‡‡xx
`
`BACKGROUND The American Society of Dermatologic Surgery (ASDS) periodically develops consensus
`documents for its members concerning various aspects of dermatologic surgery. Advances in photodynamic
`therapy (PDT) have been many and PDT use has been established in a variety of skin conditions.
`
`OBJECTIVE The ASDS board of directors proposed a committee of experts in the field to develop consensus
`documents on different treatments. An expert panel reviewed the literature on PDT and discussed the findings.
`The consensus was reached with evidence-based recommendations on different clinical applications for PDT.
`
`PATIENTS AND METHODS This consensus document includes discussions regarding PDT, including different
`photosensitizers and various light source activators, historical perspective, mechanism of action, various ther-
`apeutic indications and expected outcomes, pre- and post-care, and management of adverse outcomes.
`
`RESULTS Photodynamic therapy is highly effective for pre-cancerous lesions, superficial nonmelanoma skin
`cancers, inflammatory acne vulgaris and other conditions. New protocols including laser mediated PDT sig-
`nificantly improve results for several indications.
`
`CONCLUSION The ASDS consensus document on PDT will be helpful for educating members on safe and
`effective PDT for a variety of indications.
`
`The authors have indicated no significant interest with commercial supporters.
`
`Photodynamic therapy (PDT) relies on the
`
`interaction between a photosensitizer, the
`appropriate activating wavelength of light, and oxygen.
`The reaction generates reactive oxygen species (ROS)
`in cells that either take up an exogenous photosensitizer
`or produce its own endogenously, causing cell death by
`necrosis or apoptosis, but minimally affects the
`surrounding tissue. Initially, PDT relied on systemic
`administration of the photosensitizer, but the advent of
`topical application revolutionized the field. The main
`types of topical photosensitizer prodrugs used for PDT
`are 5-aminolevulinic acid (5-ALA) or its derivatives.
`
`The main derivative used is methyl aminolevulinate
`(MAL) which is demethylated by the target tissue to
`produce ALA. Exogenously applied ALA and MAL
`bypass the intracellular rate-limiting step in the heme
`synthesis pathway to produce the actual
`photosensitizers, protoporphyrin IX, and other
`porphyrins. Over the past 100 years, PDT has evolved
`into a safe and effective dermatologic treatment
`option for actinic keratosis/cheilitis, superficial
`nonmelanoma skin cancer (NMSC), and more recently,
`photoaging, acne, rosacea, sebaceous hyperplasia, and
`verrucae.1–4 Topical PDT offers the advantage, when
`
`*Department of Dermatology, Henry Ford Hospital, Detroit, Michigan; †English Dermatology, Gilbert,
`Arizona; ‡Cosmetic Laser Dermatology, San Diego, California; xUniversity of California, San Diego, California; ¶Gold
`Skin Care Center, Nashville, Tennessee; kCosmetic Laser Dermatology, San Diego, California; #Department of
`Dermatology, University of California, San Diego, California; **Cranley Clinic, London, United
`Kingdom; ††Dermatology Associates, Maui, Hawaii; ‡‡Dermatology, Laser, and Vein Specialists of the Carolinas,
`Charlotte, North Carolina; xxWake Forest School of Medicine, Winston Salem, North Carolina
`ISSN: 1076-0512· Dermatol Surg 2016;42:804–827· DOI: 10.1097/DSS.0000000000000800
`
`© 2016 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
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`compared with other destructive modalities, of being
`able to selectively and effectively target and
`simultaneously treat lesions over large surface areas
`with little or no risk of scarring. Furthermore, PDT has
`also expanded outside of the field of dermatology and is
`now used as adjuvant therapy to treat pulmonary,
`respiratory tract, neural, and urinary tract tumors, and
`vitreoretinal disease.
`
`In 1990, Kennedy reported the use of 5-ALA and
`visible light for topical PDT treatment of the skin.
`ALA was revolutionary because it easily penetrated,
`damaged or abnormal stratum corneum and rapidly
`cleared. Using a single application to treat basal cell
`carcinoma (BCC), Kennedy and colleagues5 were able
`to achieve a 90% complete response rate.
`
`Historical Perspective
`
`Ancient civilizations have known for thousands of years
`that they could combine different plants with sunlight
`to treat various skin diseases. It was not until about 100
`years ago that Hermann von Tappeiner coined the
`term “photodynamic action” to describe an oxygen-
`dependent reaction following photosensitization.4 He
`noted that in the absence of oxygen, dye and light alone
`did not cause cell death. He continued to develop the
`concept of PDT and eventually described the first cases in
`humans, using eosin as the photosensitizer to treat
`various skin conditions, including condyloma lata and
`NMSC. Over the years, many photosensitizers have
`been used, and the most studied agent was hematopor-
`phyrin. However, hematoporphyrin had to be adminis-
`tered intravenously and was cleared from tissue very
`slowly, resulting in prolonged phototoxicity.
`
`Basic Principles of Photodynamic Therapy
`
`Photodynamic therapy is the interaction among 3 ingre-
`dients: light, a photosensitizer, and oxygen (Figure 1).
`After exposure of the photosensitizer to light containing
`its action spectrum, ROS, especially singlet oxygen rad-
`icals, are generated. The ROS affect all intracellular
`components, including proteins and DNA, resulting in
`necrosis or apoptosis.6 The accumulation of the photo-
`sensitizer within cells, where it is preferentially produced
`or taken up, results in tissue destruction while minimizing
`surrounding tissue damage, often resulting in an out-
`standing cosmetic result.
`
`Photosensitizers
`
`5-aminolevulinic acid has revolutionized the field of
`PDT. It has a low molecular weight that allows it to
`easily penetrate the stratum corneum. Maximum
`
`Figure 1. Mechanism of PDT. Exogenous aminolevulinic acid (ALA) enters the porphyrin-heme pathway and is converted
`endogenously into the PpIX. Once PpIX is activated by the proper wavelength of light, it produces singlet oxygen free
`radicals, which destroy the target cell (courtesy of Ali M. Rkein, MD).
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`concentration of photosensitizer protoporphyrin IX
`(PpIX) has been shown to occur about 6 hours after the
`end of the 4-hour incubation of ALA 20%7,8 and is
`cleared from the skin within 24 to 50 hours of appli-
`cation.9 ALA is the first compound synthesized in the
`porphyrin–heme pathway and is converted endoge-
`nously into the PpIX. Once PpIX is exposed to its
`visible light action spectra (including PpIX absorption
`peaks at 400–410 nm and 635 nm), ROS are gener-
`ated, which destroy the target cell. Although the heme
`synthesis pathway is controlled by ALA synthase,
`exogenous ALA bypasses this rate-limiting enzyme
`and overwhelms the cell’s ability to convert PpIX into
`heme. ALA is thought to preferentially target tumors
`of epithelial origin because of their defective epidermal
`barrier and slower conversion of PpIX into heme. In
`the United States, ALA is available as a 20% solution
`and is marketed under the trade name Levulan (DUSA
`Pharmaceuticals, Inc., Wilmington, MA). It is FDA
`approved since 1999 and approved for the treatment
`of nonhyperkeratotic actinic keratosis (AKs) on the
`face and scalp in conjunction with a blue light
`source.10 It is supplied as a cardboard tube housing 2-
`sealed glass ampules, one containing 354 mg of d-ALA
`hydrochloride powder and the other 1.5 mL of sol-
`vent.6 These separate components are mixed within
`the cardboard sleeve just before use.
`
`An alternative to ALA is the methyl ester form, MAL.6
`The presence of methyl ester group makes the molecule
`
`more lipophilic and enhances penetration; however,
`MAL must be demethylated back to ALA by intra-
`cellular enzymes. Although this may limit the avail-
`ability of ALA, MAL has been shown to reach
`maximal intracellular concentrations of PpIX quickly,
`allowing a shorter incubation period. In the Unites
`States, MAL was available for a brief period of time as
`a 16.8% cream and marketed under the trade name
`Metvixia (Galderma Laboratories, L.P., Ft. Worth,
`TX). However, it is currently unavailable in the US
`market, but remains widely used in Europe.
`
`Light Source
`
`Several light sources, including coherent and inco-
`herent light, have been used in PDT. PpIX has a strong
`absorption peak between 405 and 415 nm (Soret
`band), along with several smaller Q bands from 500 to
`630 nm; the last peak is at 635 nm (Figure 2). Blue
`light, which includes the wavelength of 405 nm, effi-
`ciently excites PpIX and is commonly used. The most
`widely available fluorescent lamp light source is the
`Blu-U (DUSA) with a peak emittance at 417 6 5 nm.11
`Because of its relatively short wavelength, blue light
`penetrates about 2 mm, whereas red light (635 nm) is
`used for thicker lesions because it has a greater than
`2-mm penetration.12 The 635-nm wavelength targets
`the last Q band; because red light does not excite PpIX
`as efficiently as blue light, a higher fluence (dose) is
`needed.7 However, the consensus group noted that
`
`Figure 2. Absorption spectrum of PpIX in the ultraviolet and visible spectrum (courtesy of David M. Ozog, MD).
`
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`clinically blue light is effective in some instances where
`you would only expect red light to work. This may be
`related to incomplete knowledge as to the number of
`photons needed to activate aminolevulinic acid. The
`reported penetration depths for various wavelengths
`of light reflect the point at which 50% of the photons
`have penetrated and the depth of an activity of the
`remaining photons is unclear with either red or blue
`light. For instance, a 488-nm argon ion laser has
`200 mm of tissue penetration compared with a 694-nm
`ruby laser which has a 1200-mm penetration depth of
`50% of the photons in white skin.13
`
`Intense pulsed light (IPL) is a source of incoherent
`light, which emits a radiation spectrum from
`approximately 500 to 1,200 nm.8 Cutoff filters allow
`customization of the delivered wavelengths. This light
`source is particularly useful in photorejuvenation,
`targeting pigment, blood vessels, and even collagen.
`Light-emitting diodes (LEDs) provide a narrower
`spectrum of light irradiation, usually in a 20- to 50-nm
`bandwidth through a compact, solid, but powerful
`semiconductor.8 Light-emitting diodes are simple to
`operate and are typically small in size, emitting light
`from the UV to IR portion of the electromagnetic
`spectrum. However, the diminutive size of most
`commercially available LED panels necessitates mul-
`tiple rounds of light illumination to treat larger areas.
`Daylight PDT is being increasingly researched and
`used, particularly in Europe.14 Combined
`with minimal incubation time, daylight PDT produces
`results with little to no discomfort to patients. In
`addition, no equipment is needed and patient time in
`clinicians’ office is minimized. Challenges include
`determining and standardizing exposure times for
`various latitudes and seasonal light variances.
`
`Lasers provide precise doses of light radiation. As
`a collimated light source, lasers deliver energy to target
`tissues at specific wavelengths chosen to mimic
`absorption peaks along the porphyrin curve. Lasers
`used in PDT include the tunable argon dye laser
`(blue–green light, 450–530 nm),15 the copper vapor
`laser-pumped dye laser (510–578 nm), long-pulse
`pulsed dye lasers (585–595 nm), the Nd:YAG KTP dye
`laser (532 nm), the gold vapor laser (628 nm), and
`solid-state diode lasers (630 nm).16,17 Fractionated
`
`O Z O G E T A L
`
`ablative lasers, although not “light sources,” are
`increasingly used to pretreat lesions, enhancing pene-
`tration and efficacy across multiple indications. The
`impressive early data are discussed in each clinical
`subsection throughout this article.
`
`It is important to consider the fluence (J/cm2) and
`irradiance (mW/cm2) that are used in PDT. The
`effective photobleaching dose for a light source of
`approximately 405 nm is 10 J/cm2, and a 10-fold
`increase, or 100 J/cm2 for a light source of 635 nm.
`This is why a typical PDT treatment with blue light
`would take less time than a treatment with red light if
`the fluences were identical. Red light requires a longer
`irradiation period because it does not excite PpIX as
`efficiently as blue light. However, many red light
`devices in use have a higher fluence compared with
`blue light devices and thus the time to treat can be quite
`similar. In addition, because PDT consumes oxygen,
`it is important to use an appropriate rate of fluence
`(i.e., irradiance) as a high irradiance may consume the
`oxygen molecules too quickly, leading to a decrease in
`efficiency.6 Some researchers believe that this signifi-
`cantly decreases the clinical effect when using lasers for
`PDT treatment. Thus, the fluence should be kept in the
`range of 150 to 200 mW/cm2 to avoid hypoxic effects
`on tissue.18,19 In fact, there is evidence to support that
`cumulative light doses of greater than 40 J/cm2 can
`deplete all available oxygen sources during the oxi-
`dation reaction, making higher doses of energy during
`PDT unnecessary.20
`
`Preoperative Care
`
`After medical or cosmetic indications for PDT have
`been ascertained, focus should be turned to peri-
`procedural details. It is imperative to obtain a proper
`patient medical history. Any history of photo-
`sensitizing disorders, poryphrias, or documented
`allergy to ALA or MAL may preclude treatment.21–24
`Because only visible light is used for activation, con-
`current use of medications known to cause toxicity
`with exposure to UV light is allowed and should not
`be an issue. Previous history of herpes simplex virus
`(HSV) should be elicited and some authors initiate
`prophylactic measures taken before the initiation of
`therapy.25 However, members of this consensus
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`group do not routinely give prophylactic therapy to
`patients with HSV history. Skin conditions, which
`promote parakeratotic scale, such as seborrheic der-
`matitis, should be treated and controlled before PDT,
`as this type of scale is more hyperproliferative and can
`absorb ALA.
`
`Many methods exist for pretreatment preparation of
`skin-cleansing regimens. Cleaning allows for a more
`uniform penetration of the ALA and subsequent
`photoactivation. Acetone is frequently used to
`degrease the skin and facilitate penetration, however,
`it has a low flash point, can be painful for open or
`eroded skin, and its availability may be limited at
`larger academic institutions. Thus, other cleaning
`agents are sometimes used. Peikert and colleagues26
`showed equal degreasing capability between acetone
`and hibiclens for prepping skin before chemical peel-
`ing. Isopropyl alcohol, soaps, alpha-hydroxy/salicylic
`acid cleansers, or towelettes can also be used.
`
`After cleansing, numerous techniques (ranging from
`noninvasive to minimally invasive) can be used to
`disrupt the stratum corneum and enhance the skin
`penetration of ALA. The trade-off of these methods is
`added time and expense of supplies as well as staffing.
`One simple method is gauze abrasion or the
`heavy-handed use of 4 · 4 gauze rubbed on the skin.
`Oscillating brushes or particle/particle-free micro-
`dermabrasion has also been reported as methods of
`enhancement of penetration.27 The use of micro-
`needling rollers has been studied and shown to promote
`ALA penetration, absorption, and activation.28 More
`recently, fractional nonablative and ablative fractional
`lasers have been used before application to enhance
`penetration, activation, and efficacy29–32 This use of
`fractional lasers to enhance delivery will be thoroughly
`discussed by indication throughout this article.
`
`The application of the topical ALA solution (after
`mixing per package insert) should be carefully consid-
`ered. Ideally, the use of the Kerastick (DUSA Pharma-
`ceuticals) cotton-tipped applicator facilitates
`placement. Application to the full face is best accom-
`plished expressing the solution onto the treatment area
`and with a gloved hand evenly wiping it over the face in
`2 coats. Care should be taken to apply within close
`
`proximity to avoid dripping solution. Because actinic
`damage is frequently present in the lateral/medial brows
`and into the frontal and sideburn hairlines, these areas
`should not be overlooked. For nonfacial areas, such as
`the extremities, occlusion has been used to increase
`penetration. This can be accomplished with plastic
`wrap or some other nonporous flexible material placed
`over the targeted area after the ALA has been applied.
`Applying a warming blanket can also enhance pene-
`tration and increase clearance of actinic keratosis as
`demonstrated in a prospective clinical trial.33
`
`Incubation times will vary and depend on the type of
`treatment (cosmetic vs medical), anatomical area trea-
`ted, the severity of the actinic damage, and patient tol-
`erance. For the treatment of actinic damage on the face,
`incubation times of 1 to 2 hours are commonly used in
`clinical practice.14,34 This reduction in treatment time
`was done primarily for patient and physician conve-
`nience as the initial studies had incubation times of 14 to
`18 hours which maximized PpIX levels in actinic tissue.
`On the scalp, typically a minimum of 2 hours is used for
`incubation. A recent multicenter randomized study
`found the median AK clearance rate at 12 weeks to be
`88.7% for extremities, when treated with ALA under
`occlusion for 3 hours and irradiated with blue light (10
`J/cm2).35 These shorter incubation times have resulted
`in reduced, but acceptable, clearance rates of actinic
`keratosis compared with initial FDA trial data. Incu-
`bation should take place in a dark room, devoid of as
`much ambient light as possible. Typically, discomfort
`during light treatment will increase with longer incu-
`bation times as additional drug is converted to active
`form. For this reason as well as cost and patient con-
`venience, many European centers have been conducting
`“daylight” PDT, where patients incubate for a much
`shorter period before spending a few hours outdoors
`for exposure rather than a device in the clinician’s
`office.36 Sunscreen is used during this time to prevent
`UV-induced sunburn because it does not interfere with
`the visible light activation of PpIX (unless it is applied
`thickly in an opaque manner). Appropriate exposure
`times have been developed for various latitudes and
`weather conditions.
`
`After incubation, the targeted area may be gently
`washed with water and a cleanser. Irradiation should
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`be performed in an appropriately sized room prefer-
`ably without windows and with low ambient light
`levels (to prevent phototoxicity or photobleaching).
`The room should also have adequate cooling and
`ventilation for the light source.
`
`Appropriate eye protection is paramount during all
`aspects of the procedure to ensure ocular safety.
`Prolonged exposure to blue and ultraviolet light is
`damaging to the retina and increases the risk of cata-
`racts.37 Red light does not seem to result in the same
`retinal toxicity, but ocular protection is still recom-
`mended. In the pivotal Phase III FDA trial for actinic
`keratosis, the fluorescent lamp light source was the
`Blu-U (DUSA) with a peak emittance at 417 6 5 nm,
`and blue-blocking goggles were worn by patients
`during irradiation.38 Because a wider variety of light
`sources are used nowadays, the type of goggles used
`must be suitable to the light source. The preference is
`for patients to use completely opaque eye protection
`to minimize exposure. All staff or providers should
`wear appropriate eyewear before entering the room.
`
`Therapeutic Applications and
`Expected Outcomes
`
`Since the advent of PDT, the list of indications has
`continued to grow. The following sections will focus
`on the treatment and expected outcomes of actinic
`keratosis, NMSC, acne, photorejuvenation, and ver-
`rucae. Please see Tables 1–4 which outline therapeutic
`applications and expected outcomes of PDT, a general
`PDT protocol, home care instructions, and typical
`settings used in PDT, respectively.
`
`Actinic Keratosis
`
`In the United States, the only FDA-approved indica-
`tion (1999) for PDT is the treatment of non-
`hyperkeratotic AKs on the face and scalp in
`conjunction with a blue light source.6 The initial
`FDA Phase II and III studies of ALA-PDT (Levulan
`Kerastick; DUSA) in the treatment of non-
`hyperkeratotic actinic keratosis on the face and scalp
`had a clearance rate of 85% to 90% after 1 to 2
`treatment sessions. The ALA was applied for 14 to
`
`TABLE 1. Indications and Expected Outcomes
`
`Indications
`
`Actinic keratosis
`
`Squamous cell in situ
`(Bowen disease)
`
`Actinic cheilitis
`
`SCC prevention in solid
`organ transplants
`Superficial BCC
`
`Nodular BCC
`Acne vulgaris
`
`Photorejuvenation
`
`Verrucae
`
`Summary of Recommendations
`
`Highly effective
`When treating head and neck, efficacy similar to, or exceeds other FDA-approved modalities
`Better cosmetic outcome when compared with cryotherapy
`Efficacy likely superior to cryotherapy and 5-FU
`Good cosmetic outcome
`Clearance rates are between 80% and 82% at 1 yr
`Conventional PDT is not very effective with clearance rates that range from 29% to 47%.
`However, with laser-assisted PDT, the clearance rates jump to 85%.
`Cyclic PDT at intervals of 1–2 months can reduce the occurrence of new lesions by 79% and
`95% at years 1 and 2, respectively.
`Highly effective and similar to simple excisions
`Very useful in treating multiple lesions
`Main disadvantage is time commitment
`May be used in specific patients when other options are not appropriate
`Highly effective in the treatment of inflammatory papules, but not comedones
`Excellent option for moderate-to-severe acne when isotretinoin is not an option
`Drawbacks include time commitment, discomfort during treatment, posttreatment erythema,
`and crusting
`Pulsed dye laser (PDL) as a light source can also help with early erythematous scars
`Excellent cosmetic results for all facets of photodamage
`Multiple other proven and accepted modalities, which are less expensive and require less time
`Very effective, but rarely used by the authors
`Reported clearance rates of hand and foot warts ranging from 56% to 100%
`Reported clearance rates of condyloma accuminata ranging from 66% to 79%
`
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`TABLE 2. Photodynamic Therapy General Treatment Protocol
`
`Patient washes the area to be treated with soap and water
`Acetone- or alcohol-soaked 4 · 4 gauze is used to remove any remaining debris and oil
`The photosensitizer is evenly applied to the entire area to be treated. A second coat of the photosensitizer can be
`applied, after the first coat has dried.
`Allow the photosensitizer to incubate for 0.5–4 hours (see below for more comprehensive recommendations)
`Activate the photosensitizer with the appropriate light source
`Patient to wash the treated area with soap and water to remove any residual photosensitizer
`The patient must stay out of the any direct sunlight for 48 h
`Repeat as needed in 2–3 wk
`
`18 hours, followed by irradiation with a blue light
`source (10 J/cm2) for 1,000 seconds. Since then, dif-
`ferent protocols have been developed to improve the
`efficacy for other indications and to reduce the dis-
`comfort and time associated with the administration
`of PDT.6 The byproduct of these reduced incubation
`time protocols is a reduction in the clearance rates seen
`in the initial FDA Phase II and III studies in most
`subsequent clinical trials. In a European multicenter,
`randomized, prospective study with 119 subjects and
`1,500 lesions, MAL-PDT was compared with cryo-
`surgery in the treatment of actinic keratosis. Patients
`were randomized to either a single treatment with
`MAL-PDT (3 hours of incubation with illumination
`with broad-spectrum red light; 75 J/cm2) or a double
`freeze–thaw cycle of liquid nitrogen. They found no
`
`significant difference between the 2 treatment modal-
`ities, but MAL-PDT provided a superior cosmetic
`result.40 Pariser and colleagues,41 in a multicenter,
`randomized, double-blind study treating AKs with
`MAL-PDT, found a clearance rate of 67% after the
`initial treatment and 90% after retreatment. Touma
`and colleagues34 examined the effect of pretreatment
`with urea (to enhance ALA penetration) and con-
`cluded that urea did not influence the therapeutic
`outcome. Finally, a recent Cochrane review found that
`ALA-PDT or MAL-PDT, with blue or red light,
`resulted in similar efficacy in the treatment of actinic
`keratosis; however, for ALA-PDT, longer incubation
`(4 hours) resulted in better results compared with
`shorter incubation time (<2 hours).42 The review also
`found that 4-hour incubation with ALA-PDT was
`
`TABLE 3. Sample Home Care Instructions for Patients Following Photodynamic Therapy
`
`Day of Treatment
`1. Remain indoors and avoid direct sunlight for 36 hours. VERY IMPORTANT!!! Do not sit by a window.
`2. Spray on Avene Thermal Spring Water often.39
`3. Wash the face twice a day with a gentle cleanser.
`4. Apply bland moisturizing cream 4 times a day.
`5. Take analgesics such as ibuprofen if there is any pain.
`6. If you have any discomfort, apply ice packs to the treated area for 5–10 minutes every few hours. This will help keep
`the area cool and alleviate any discomfort, as well as help keep down any swelling. Swelling will be most evident
`around the eyes and is usually more prominent in the morning.
`7. Redness of the face may be very intense for the first day or 2.
`Day 2–7:
`1. Wash the face twice a day with a gentle cleanser
`2. The skin will feel dry and tightened; a bland moisturizing cream should be used twice a day.
`3. You may begin applying make-up once crusting has healed. The area may be red for 3–5 days. If make-up is
`important to you, please use mineral make-up, which is all natural, inert, and small anti-inflammatory and acts as
`a concealer with sunscreen. It is especially effective to mask redness.
`4. When outdoors, use a “physical block” sunscreen with zinc oxide or titanium dioxide and a minimum SPF 30.
`Consult with your skin care professional for a sunscreen recommendation.
`If you have any questions or concerns, please do not hesitate in contacting our office.
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`TABLE 4. Photodynamic Therapy Specific Treatment Protocols for Different Indications
`
`Indication
`
`Topical
`Photosensitizer
`
`Incubation
`Period
`
`Light
`Source
`
`Actinic keratosis
`
`ALA
`
`1–4 h
`
`Blue light
`
`1–4 h
`
`Red light
`
`Dose
`
`Comments
`
`10 J/cm2
`
`Requires 1–2 sessions of PDT for
`optimal results
`75–150 J/cm2 Sunscreen necessary for daylight
`PDT
`
`Bowen disease
`
`Superficial BCC
`
`Acne vulgaris
`
`Photorejuvenation
`
`MAL
`ALA
`
`MAL
`ALA
`
`MAL
`ALA
`
`MAL
`ALA
`
`MAL
`
`0.5 h
`1–3 h
`4 h
`
`3 h
`3–6 h
`
`3 h
`3 h
`
`3 h
`30 min–3 h
`
`30 min–1 h
`
`Daylight
`Red light
`Red light
`
`2 h
`37–75 J/cm2
`$100 J/cm2
`
`Red light
`Red light
`
`75–100 J/cm2
`$60 J/cm2
`
`Red light
`Blue light
`Red light
`Red light
`Blue light
`Red light
`Red light
`
`37–75 J/cm2
`10 J/cm2
`37 J/cm2
`37 J/cm2
`10 J/cm2
`37 J/cm2
`37 J/cm2
`
`Requires 2–3 sessions of PDT for
`optimal results
`
`Requires 2–3 sessions of PDT for
`optimal results
`
`2–3 treatments, repeated biweekly
`
`2–3 treatments, repeated monthly
`
`ALA, aminolevulinic acid; BCC, basal cell carcinoma; MAL, methyl aminolevulinate; PDT, photodynamic therapy.
`
`significantly more efficacious than cryotherapy, but
`1-hour incubation with ALA-PDT (blue light or pulsed
`dye laser) was not significantly different than 0.5%
`5-fluorouracil (5-FU). Lastly, the review found that
`MAL-PDT had similar efficacy regardless of the light
`source used (red light, broadband visible light with
`water-filtered infrared A, and daylight).
`
`In an attempt to increase AK clearance from a single
`PDT treatment, 2 of the authors (M.P.G. and S.G.F)
`showed that multiple sequential laser and light sources
`(IPL, PDL, blue light, and red light) led to significantly
`greater AK clearance than that achieved with a single
`light source (blue light), without significant differences
`in posttreatment adverse events.17 They hypothesized
`that the sequential use of different light sources affects
`multiple absorption peaks of PpIX, perhaps similarly
`to daylight PDT which activates PpIX at multiple
`wavelengths.43,44
`
`Several studies to increase the efficacy of PDT
`through the use of fractional surface ablation to
`increase the penetration of ALA through the stratum
`corneum have been performed. Each study shows
`superiority with ablative fractional laser pre-
`
`treatment. Ko and colleagues treated 40 patients
`with 236 facial AKs in a prospective randomized
`nonblinded trial. All the patients were treated with
`MAL-PDT, but 23 of the patients with 135 AKs were
`pretreated with 2,940-nm ablative fractional
`Erbium:yttrium-aluminum-garnet (Er:YAG) laser
`(ablation depth of 300–550 mm, 22% treatment
`density and a single pulse).45 The patients were
`followed up for 1 year. They found that the pre-
`treatment with the fractional Er:YAG laser was
`significantly more effective in treating AKs of all
`grades (86.9% vs 61.2%), but was even more pro-
`nounced in thick hyperkeratotic lesions (69.4% vs
`32.5%). They also noted a much lower recurrence
`rate in the laser group compared with the traditional
`MAL-PDT group (9.7% vs 26.6%). More erythema
`and hyperpigmentation were seen in the laser group,
`but were mild and well tolerated. In addition, Choi
`and colleagues treated 93 patients with facial and
`scalp AKs and randomized to traditional MAL-PDT
`with 3 hours of incubation, or Er:YAG ablative
`fractional laser-assisted MAL-PDT (AFL-PDT) with
`2 or 3 hours of MAL incubation. Patients were
`followed at 3 and 12 months. At 3 months, they
`noted that the 3-hour AFL-PDT was significantly
`
`4 2 : 7 : J U L Y 2 0 1 6
`
`811
`
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`

`P H O T O D Y N A M I C T H E R A P Y
`
`more efficacious in the treatment of AKs when
`compared with 2-hour AFL-PDT and traditional
`3-hour MAL-PDT, 91.7%, 76.8%, and 65.6%,
`respectively. This trend remained true at 12 months.
`Thus, they recommended 3-hour AFL-PDT over
`short-incucation AFL-PDT and traditional
`MAL-PDT.46 Togsverd-Bo and colleagues47 com-
`bined fractional Er:YAG with daylight PDT in
`transplant patients for treatment of AKs. Sixteen
`patients with 542 AKs in field-cancerized skin of the
`scalp, chest, and extremities were treated. Complete
`response rates in areas pretreated with fractional
`Er:YAG followed by daylight PDT had the highest
`efficacy at 74% 3 months after treatment compared
`with conventional PDT without laser and laser
`alone. The density of the fractional laser was
`remarkably low at 2% to 4% and pain averaged 0/10
`for this arm of the study. Authors concluded that this
`protocol is quite tolerable and may be preferable for
`treatment of difficult AKs in organ transplant
`patients.
`
`Actinic Cheilitis
`
`Actinic cheilitis is a premalignant condition localized
`to the lips, which can progress to invasive squamous
`cell carcinoma (SCC), similar to AKs on the skin. In
`2015, Yazdani Abyaneh and colleagues48 completed
`a systemic review that examined the treatment of
`actinic cheilitis with PDT. They examined 15 case
`series that included 242 patients. Both ALA and MAL
`were used, with incubation periods that ranged from 2
`to 4 hours. Red light (630 nm) irradiation was used for
`both ALA and MAL; range 37 to 80 J/cm2. When they
`examined the studies that evaluated for complete
`clinical response, they found the rate to be 62% with
`a follow-up period ranging from 3 to 30 months. The
`studies that examined histological clearance found
`a cure rate of 47% with a follow-up period ranging
`from 1.5 to 18 months. The most common reported
`adverse events reported were pain and burning, which
`resolved within 2 weeks. They also reported good to
`excellent cosmetic results in most patients. This result
`is lower than reported cure rates of up to 96% to 99%
`with surgical excision; however, excision can be
`associated with a marked increase in morbidity,
`including scarring.49
`
`Choi and colleagues29 examined the efficacy of
`ablative fractional laser-assisted PDT of actinic
`cheilitis. They enrolled 33 patients with actinic
`cheilitis, to either pretreatment with Er:YAG
`(300 mm ablation depth, 22% treatment density,
`and a single pulse) followed by MAL-PDT or 2
`sessions of MAL-PDT, 1 week apart. Methyl ami-
`nolevulinate was applied under occlusion for 3
`hours, followed by red light irradiation (636 nm,
`37 J/cm2). Patients