Temperature-Modulated Photodynamic Therapy for the
`Treatment of Actinic Keratosis on the Extremities:
`A Pilot Study
`Andrea Willey, MD,*† R. Rox Anderson, MD,‡x and Fernanda H. Sakamoto, MD, PhD‡x
`
`BACKGROUND The efficacy of photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA) for the
`treatment of actinic keratosis (AKs) is lower on the distal extremities compared with the head and neck areas.
`The strong temperature dependence of porphyrin synthesis in biologic tissue suggests that heating skin during
`incubation may improve the efficacy of PDT, particularly in areas where biologic temperatures are naturally
`lower. The aim of this study was to evaluate the efficacy and tolerability of temperature-modulated PDT for the
`treatment of AKs on the extremities.
`
`METHODS In this IRB-approved, single-center study, the upper or lower extremities of 20 subjects were
`treated with 20% ALA under occlusion, followed by 10 J/cm2, 417-nm blue light. One of the 2 extremities treated
`was heated during the 1-hour incubation. Outcome measures included lesion counts, tolerability, and global
`improvement at baseline, 1 week, and 2 and 6 months after treatment.
`RESULTS The median temperatures of the heated and control sides were 38.8°C and 29.4°C, respectively.
`The median clearance for the heated side was significantly greater than the control side at 2 and 6 months
`(p < .0001). Typical PDT side effects were greater on the heated side compared with the control yet were well
`tolerated by all subjects.
`
`CONCLUSION Warming the skin during incubation of ALA seems to improve the efficacy of PDT in the treat-
`ment of AKs on the extremities and is well tolerated when heat application is controlled within the limits of safety.
`
`The efficacy of cutaneous photodynamic therapy
`
`(PDT) using topical 5-aminolevulinic acid (ALA)
`in the treatment of AK has been demonstrated in a large
`number of clinical trials.1–10 Emerging literature
`supporting long-term response rates underscores the
`potential benefits of PDT in the management of
`nonmelanoma skin cancer.11–17 Photodynamic therapy
`is particularly advantageous for the treatment of large
`surface areas and is especially suitable for the treatment
`of multiple actinic keratoses (AKs) and areas of field
`cancerization.18,19 Published studies have demonstrated
`high clearance rates with multiple topical PDT
`
`regimens that are comparable with other topical
`therapies used for the treatment of AKs, particularly
`on the face and scalp.8,9,20 However, the efficacy of
`PDT on the extremities is greatly reduced.1,2,10,21,22
`The strong relationship between temperature and
`porphyrin synthesis in biologic tissue23–28 suggests that
`increasing the temperature of the skin during the
`incubation of ALA may improve the efficacy of PDT,
`particularly for areas that are naturally lower in
`temperature such as the distal extremities.
`5-aminolevulinic acid is a precursor drug, whereas its
`metabolite, protoporphyrin IX (PpIX), is the active
`
`*Andrea Willey, MD, PMC, Surgical & Aesthetic Dermatology, Sacramento, California; †Department of Dermatology,
`University of California Davis, Sacramento, California; ‡Department of Dermatology, Wellman Center for Photomedicine,
`Massachusetts General Hospital, Boston, Massachusetts; xDepartment of Dermatology, Harvard Medical School, Boston,
`Massachusetts
`
`A. Wiley’s employer received a research grant, equipment loan, and study drug from DUSA Pharmaceuticals, Inc. A. Willey
`is a member of the scientific advisory board for DUSA pharmaceuticals. The other authors have indicated no significant
`interest with commercial supporters.
`
`© 2014 by the American Society for Dermatologic Surgery, Inc.· Published by Lippincott Williams & Wilkins·
`ISSN: 1076-0512· Dermatol Surg 2014;40:1094–1102· DOI: 10.1097/01.DSS.0000452662.69539.57
`
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`photosensitizer. Like many metabolic pathways in the
`body, the conversion of ALA can be modulated by
`temperature. The aim of this study was to evaluate the
`efficacy and tolerability of temperature-modulated
`PDT for the treatment of AKs on the distal extremities.
`
`Methods
`
`Preliminary Determination of Skin Temperature
`Exposed to Heating Pad in a Single Individual
`
`The temperature of lower extremity skin on a healthy
`individual with normal vascular tone was measured
`by a single investigator (A.W.) during a 1-hour
`exposure to a typical heating pad to determine the
`appropriate control setting for use during the incu-
`bation of ALA. The ambient temperature was recor-
`ded as measured with an Acurite temperature monitor
`(Model 00325; Chaney Instrument Co., Lake Geneva,
`WI) that measures a range of 0°C to 50°C at 16% to
`99% of relative humidity. The skin surface temper-
`ature was measured with a calibrated digital ther-
`mocouple meter (Traceable model 4233CP; Cole–
`Parmer, Vernon Hills, IL) with a Type K probe
`measuring a range of 250°C to 750°C with an
`accuracy of 61°C between 0°C and 500°C. The
`thermocouple probe was taped to the anterior surface
`of the low leg, which was then wrapped with clear
`plastic wrap (Saran; SC Johnson, Racine, WI). The
`extremity was heated by applying a covered Under-
`writers Laboratories (UL)–tested heating
`pad (Sunbeam with UltraHeat Technology; Jarden
`Consumer Solution, Boca Raton, FL). The skin
`temperature was measured at 1-minute intervals for
`a duration of 1 hour for each control setting of “low,”
`“medium,” and “high.” The skin was allowed to
`return to baseline temperature before measurement
`at each setting.
`
`The ambient temperature measured 20°C and 65% of
`relative humidity. The baseline skin temperature of
`the extremity measured 32°C. When the heat pad was
`set on “low,” the skin measured 35°C at 1 minute and
`reached a maximum of 38°C at 15 minutes. At
`a setting of “medium,” the skin measured 36°C at
`1 minute and a maximum of 39°C at 14 minutes. At a
`setting of “high,” the skin measured 37°C at 1 minute
`
`W I L L E Y E T A L
`
`and a maximum of 42°C at 14 minutes. Subjectively,
`the heating pad was tolerated well on “low” and
`“medium”; however, it became uncomfortably warm
`after a few minutes when set on “high,” which corre-
`lated at a temperature of 40°C. Based on these findings,
`the setting of “medium” was chosen as for the study in
`clinical subjects.
`
`Enrolment Criteria
`
`Subjects older than 18 years with at least 10 AK lesions
`on their arms or legs were enrolled in this IRB-approved,
`single-center study, conducted by a single investigator
`(A.W.) at a single center in Fairfield, California.
`Informed consent was obtained in compliance with the
`ethical guidelines of the 1975 Declaration of Helsinki
`and HIPPA regulations.29,30 Actinic keratosis lesion
`areas must not have been treated for at least 1 year
`before enrolment. Subjects were excluded if they met
`the following criteria during the study period: preg-
`nancy, known history of photosensitivity, sensitivity to
`ALA or vehicle components, tanning bed exposure,
`treatment with systemic immunosuppressant, or
`retinoid medications.
`
`Treatment Protocol
`
`Areas to be treated were swabbed with acetone and
`gauze and allowed to dry. Topical 20% 5-ALA
`(Levulan Kerastick; Dusa Pharmaceuticals, Inc.,
`Wilmington, MA) was applied to the entire forearm skin
`and occluded with plastic wrap (Saran; SC Johnson).
`One stick (1.5 mL) was used to cover each distal
`extremity. A covered UL-tested heating pad (Sunbeam
`with UltraHeat Technology; Jarden Consumer Solu-
`tion, Boca Raton, FL) set at “medium” was wrapped
`around 1 randomly selected extremity (right or left)
`(Figure 1) during the 1-hour incubation. The contra-
`lateral extremity (control) was prepared in the same
`manner, wrapped in plastic, and incubated at room
`temperature. Control and preheated extremities were
`randomly assigned by alternating sides at the time of
`enrolment. After 1 hour, both of the treated sites
`(heated and control) were irradiated with 10 J/cm2 blue
`light (BLU-U; Dusa Pharmaceuticals, Inc.) for 1,000
`seconds with the light positioned 2 to 4 inches from the
`skin surface. During light irradiation, the treated areas
`were cooled by a small portable fan set on a mayo
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`
`Figure 1. (A) Right arm of Subject 3 at baseline. (B) Left arm of Subject 3 at baseline. (C) Right arm of Subject 3 one week after
`PDT (heated). Note the increased PDT reaction on heated side compared with control at 1 week, despite similar baseline
`lesion counts. (D) Left arm of Subject 3 one week after PDT (control).
`
`stand for comfort. The skin temperature was measured
`through the plastic wrap at baseline and at 15-minute
`intervals throughout the incubation period (by quickly
`lifting up the heating pad and replacing it) using an
`infrared noncontact thermometer (Raytek Minitemp
`MT4; Fluke Corporation, Everett, WA) that measures
`temperatures between 218°C and 275°C with an
`accuracy of 62°C at ambient temperatures of 0°C and
`50°C. Lesions were counted at baseline and at 2 and 6
`months after treatment by a single investigator (A.W.).
`Significant differences in lesion counts were determined
`by Friedman test and the Wilcoxon signed-rank test
`using p = .05 as the cutoff level.
`
`Standardized photographs of each extremity were
`taken with a high-resolution digital SLR camera (EOS
`5D Mark II; Canon Inc., Tokyo, Japan) with a 21.1
`megapixel CMOS sensor, EF 100 mm f/2.8 USM
`macro lens, and MR-14EX macro ring flash. Global
`changes in the treatment area were evaluated at baseline,
`1 week, and 2 and 6 months by an investigator (F.H.S.)
`who was blinded to treatment assignments assessing
`photographs viewed on a 27-inch monitor with 2,560 ·
`1,440 pixels and RBG color mode (iMac; Apple Inc.,
`Cupertino, CA). For quantitative analysis, photographs
`were analyzed for the measurement of affected area
`using the WCIF-ImageJ 1.44 software (Wayne
`Rasband, National Institutes of Health). To increase
`
`the accuracy of photographic analysis, for each image,
`the treated field was measured and each apparent AK
`was manually marked by the blinded evaluator (F.H.S.)
`and measured. Size variations due to slight change in
`positions of photographs were minimized by collecting
`a value relative to the treated area. For every photo-
`graph, the total area affected was compared with its
`baseline. Statistical analysis was performed using
`2-factor ANOVA to explore the differences in affected
`area at 1 week, 2 months, and 6 months compared with
`baseline, and Bonferroni post hoc analysis was used to
`locate the difference when ANOVA demonstrated
`a significant interaction. In all evaluations, a significant
`difference was accepted at a value of p < .05.
`
`Adverse effects, including erythema, edema, stinging/
`burning, blisters/crusting, hyperpigmentation, and
`hypopigmentation were graded on a scale of 1 to 4 (1 =
`mild and 4 = severe) and assessed immediately after
`treatment, 5 minutes, 1 week, 2 months, and 6
`months after treatment. At the 6-month follow-up
`visit, subjects evaluated overall treatment satisfaction
`and acceptability of treatment time, adverse effects,
`and duration of adverse effects.
`
`Results
`
`Twenty subjects aged 57 to 90 years (median, 70) were
`enrolled in this study between June 22, 2010 and June
`
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`W I L L E Y E T A L
`
`15, 2011. Subjects included 5 women and 15 men with
`skin Type II. Areas treated included the low legs of 3
`subjects and the forearms and dorsal hands of 24
`subjects. All 20 subjects completed the 6-month study.
`
`PDT-heated treatment effect persisted throughout the
`follow-up period. Clinical photographs of a typical
`subject at baseline, 1 week, and 6 months are pre-
`sented in Figures 1 and 2.
`
`The temperature of the heated side during the 1-hour
`incubation period ranged from 36.4°C to 40.6°C
`(median, 38.8°C). The temperature of the control side
`(averaged more than the 1-hour incubation period)
`ranged from 27.7°C to 33.4°C (median, 29.4°C).
`Throughout the 1 hour incubation period, the heated
`side increased in temperature on an average of 9.4°C,
`whereas the control side increased in temperature on
`an average of 1.4°C.
`
`The median lesion counts and percent differences at
`baseline and 2 and 6 months are summarized in
`Table 1. Lesion counts ranged from 6 to 170 on the
`heated side and 4 to 105 on the control side. The
`median baseline lesion count on the heated side (29.5)
`was not significantly different (p = .9843) from the
`median baseline lesion count for the control side
`(32.0). Compared with baseline, the median lesion
`counts for both the heated side and the control side
`was significantly lower at 2 months (p < .0001) and at
`6 months (p < .0001). In comparing the reduction in
`lesion counts on the heated versus the control side, the
`median difference from baseline (%) on the heated
`side was significantly greater than the median dif-
`ference from baseline (%) on the control side at
`2 months (p < .0001) and at 6 months (p < .0001).
`The median counts at 2 months and at 6 months did
`not differ significantly (p = .5195), indicating that the
`
`Blinded evaluation of standardized photographs
`assessing global changes in treatment effect demon-
`strated a significant difference in the area affected
`by treatment on the heated side compared with the
`control side, consistent with an increased PDT
`reaction on the heated side at 1 week compared with
`baseline. The global differences in the area affected
`by treatment in the heated versus control side were
`significant at 2 months when compared with baseline
`but not at 6 months.
`
`Adverse Effects
`
`The treatment was well tolerated by all subjects.
`Adverse effects of the heated and control sides were
`graded on a scale of 1 to 4 (1 = mild and 4 = severe).
`Median scores at baseline compared with scores at
`0 minutes, 5 minutes, and 1 week after treatment are
`shown in Table 2.
`
`Significant differences in erythema and stinging/
`burning were seen on the heated versus control side
`5 minutes after PDT (p = .0107 and .0039, respec-
`tively). At 1 week after PDT, significant differences
`were seen in erythema and oozing/crusting (p = .0010
`and .0039, respectively). There were no significant
`differences in dyspigmentation, scaling, or edema
`between the heated and control side at any time point.
`
`TABLE 1. Median Lesion Counts and Percent Differences From Baseline at 2 Months and 6 Months
`
`Median Lesion Counts*
`
`†Percent Difference‡
`
`Heated
`
`Control
`
`2 Months
`
`6 Months
`
`Baseline 2 Months 6 Months Baseline 2 Months 6 Months Heated
`x
`x
`x
`x
`x
`x
`7.5 (9.6)
`88.0 (14.8)
`p < .0001
`
`x
`29.5 (26.8)
`p < .0001
`
`4.0 (5.0)
`
`4.0 (3.6)
`
`32.0 (35.0)
`p < .0001
`
`9.5 (10.3)
`
`Control
`
`Heated
`
`Control
`
`x
`
`70.5 (28.9)
`
`x
`
`x
`88.0 (12.8)
`p < .0001
`
`67.5 (28.8)
`
`*Friedman test.
`†([Baseline count 2 2-month or 6-month count]/baseline count) · (100).
`‡Wilcoxon signed-rank test.
`xMedian (IQR); IQR, interquartile range, a measure of dispersion; IQR = 75th percentile 2 25th percentile.
`
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`acceptable.” Review of the medical history revealed
`a long history of iron deficiency, thyroid disease,
`hypertension, and arthritis. Medications included
`levothyroxine, hydrochlorothiazide, and diclofenac,
`which were started 4 days before PDT.
`
`Another subject demonstrated a marked reduction in
`hair (more prominent on the heated side) 1 week after
`treatment, which regrew by the 2-month follow-up
`visit. Although not prospectively evaluated nor
`graded, subtle reversible hair loss was also noted in the
`photographs of other subjects.
`
`Discussion
`
`It is no surprise that the synthesis of porphyrins in
`the heme biosynthetic pathway is a temperature-
`dependent process. Indeed, biologic processes are
`highly temperature dependent, with enzymes func-
`tioning at ideal temperatures that govern the rate
`at which chemical reactions occur to support the
`“biochemistry of life.” In general, for a 10°C change
`in temperature, the metabolic rate in the human body
`will change by a factor of 2 to 3, increasing with
`elevated temperatures and decreasing at lowered
`temperatures. Yet, the strong temperature depen-
`dence of porphyrin production and its clinical
`relevance has only recently been recognized.23–28
`
`In 1999, using fluorescence spectroscopy, Moan and
`colleagues demonstrated that the production of pro-
`toporphyrin IX (PpIX) increased nearly twofold when
`the temperature of normal murine skin in vivo was
`increased from 37°C to 42°C after a 3-hour incuba-
`tion of 20% ALA and was increased fourfold after
`a 6-hour incubation.23 Although PpIX concentration
`peaked after 3 hours, the majority of PpIX was pro-
`duced after 1 to 2 hours. Importantly, no PpIX was
`produced at 12°C. This group then demonstrated in
`WiDr cells and in murine skin a twofold to threefold
`increase in PpIX production at 36°C to 7°C compared
`with 28°C to 32°C, concluding that conversion of
`ALA to PpIX is significantly reduced at 30°C.23–25
`Protoporphyrin IX fluorescence was detectible 6 to
`10 minutes after incubation of ALA at 37°C.25 Further
`study of human forearm skin in vivo demonstrated
`a 50% increase in PpIX production when the
`
`Figure 2. (A) Right arm of Subject 3 six months after PDT
`(heated). Note increased clearance of AKs on the heated
`side compared with control. (B) Left arm of Subject 3 six
`months after PDT (control). Note early recurrence of AK
`lesions.
`
`The median subject satisfaction score at 6 months was
`slightly higher in the control side (2 vs 1), but the dif-
`ference did not achieve significance (p = .0781). Treat-
`ment time was acceptable to all 20 subjects who
`responded. When asked if adverse effects and side effects
`were acceptable, 18 subjects agreed totally, 1 subject
`agreed a little, and 1 subject neither agreed nor dis-
`agreed. Duration of side effects was acceptable to 18
`subjects (totally agree), whereas 2 subjects agreed a little.
`
`One subject developed significant erythema and blis-
`ters on both arms (score of 4 on the heated side and 3
`on the control side). The blisters resolved with the use
`of emollients for 2 weeks after treatment. Lesion
`clearance was near complete at 2 and 6 months after
`treatment. This subject graded the overall satisfaction
`with treatment as “excellent,” and graded accept-
`ability of side effects as “neither acceptable nor
`unacceptable” (neutral), and the duration of side
`effects and the time required for treatment as “totally
`
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`TABLE 2. Statistical Comparison of Adverse Effects on Heated and Control Sides
`
`p Value (Heated vs Control)*
`
`Adverse Effect
`
`Baseline
`
`Immediately
`After Treatment
`
`5 Minutes
`After Treatment
`
`Erythema
`Edema
`Stinging/burning
`Oozing/crusting
`Scaling/dryness
`Hyperpigmentation
`Hypopigmentation
`
`1.000†
`
`1.000†
`1.000†
`1.000†
`1.000†
`1.000†
`1.000†
`
`—
`
`—
`.0078‡
`—
`—
`—
`—
`
`Scale 1 to 4 in which 1 = mild and 4 = severe.
`
`*Wilcoxon signed-rank test.
`
`†Not significant.
`
`‡Significant.
`
`.0107‡
`
`.5000†
`.0039‡
`—
`—
`—
`—
`
`1
`Week
`
`.0010‡
`
`.5000†
`.5000†
`.0039‡
`.6250†
`1.000†
`1.000†
`
`2
`Months
`
`6
`Months
`
`.5000†
`
`1.000†
`1.000†
`1.000†
`1.000†
`1.000†
`1.000†
`
`1.000†
`
`1.000†
`1.000†
`1.000†
`.7500†
`1.000†
`1.000†
`
`temperature was increased from 31°C to 36°C that
`was significant after 2 hours of incubation.24
`
`Subsequent study by Van den Akker and colleagues27
`demonstrated that the penetration of 20% ALA
`through murine skin in vitro was increased at 37°C
`compared with 32°C after 1 hour of incubation. Further
`in vivo study of 6 human subjects’ back skin maintained
`at 15°C, 25°C, 31°C, and 41°C confirmed the
`increasing fluorescence of PpIX with increasing tem-
`perature, with little or no PpIX produced at 15°C. These
`authors conclude that the increase in PpIX fluorescence
`is due to the increase in skin penetration and increased
`cellular uptake and intracellular enzyme activity.
`
`More recently, Yang and colleagues28 studied the
`influence of temperature from 20°C to 50°C on ALA
`penetration and PpIX production in keratinocytes
`in vitro. Cell death increased as temperature increased,
`with the rate of apoptosis and morphological photo-
`toxic effects increasing with temperatures beyond
`38°C in PDT-treated cells. These studies clearly dem-
`onstrate that elevating temperature augments photo-
`dynamic reactions in keratinocytes in vitro and serve
`as a foundation for clinical practices using hyper-
`thermia to enhance the effectiveness of PDT.
`
`The skin is a vital thermoregulatory organ of the body,
`modulating the flow of heat through the insulating
`
`shell and the surrounding environment through com-
`plex mechanisms of constriction and dilation of cuta-
`neous blood vessels under sympathetic and adrenergic
`control.31,32 Core body temperatures are maintained
`in the fairly narrow range of 37.2°C to 37.7°C33 in
`young healthy adults despite highly variable ambient
`conditions. Skin temperature, averaged throughout
`the body surface, is typically 6°C to 7°C below that of
`the body’s core.34,35 Under normal resting conditions,
`temperatures of the skin range from 27.5°C to 35.5°C
`depending on the location, with the lowest temper-
`atures on the distal extremities and the highest on the
`head and trunk areas.36 Tonic vasoconstriction of
`cutaneous vessels aimed at minimizing heat loss leads
`to cooling of the skin and reduced metabolic activity
`at typical domestic room temperatures of 24°C to
`28°C.37,38 Ambient temperatures of 20°C are typical
`for most offices, however, vary greatly throughout
`the day, in different rooms, geographic regions, and
`seasons (OSHA recommends 20–24.4°C for offices,
`cooler for hospital settings).39 The temperature of
`human skin uniquely varies parabolically with
`changes in ambient temperatures through highly
`responsive reflex control of vascular tone.31 Local
`warming of the skin causes a direct and substantial
`vasodilation in the area being warmed,38 with max-
`imal dilation at 42°C in young healthy persons.32
`Thus, human skin is highly sensitive and readily
`responsive to changes in local temperature within
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`a range that is relevant to porphyrin synthesis and is
`likely highly relevant to the efficacy of cutaneous PDT
`under ordinary circumstances, even in the absence of
`adjunctive skin warming.
`
`Fundamentally, PDT depends on 3 components: an
`active photosensitizer, oxygen, and light (energy). The
`effects of heat-induced vasodilation might also result
`in an increase of oxygen biodistribution, contributing
`to a higher PDT effect.
`
`Importantly, the same thermoregulatory processes in
`skin that maintain homeostasis also provide vital pro-
`tection from potential thermal injury.34,40 Several studies
`have tried to determine the threshold of burn injury in
`skin with local heat exposure.41–45 In the most classic
`study conducted by Moritz and Henriques,41 it was
`determined that a continuous contact for 8 hours at
`43°C was required to create a burn on the forearm skin
`of healthy volunteers. Others have similarly concluded
`that 43°C is the safe limit for prolonged exposure to
`a hot object in healthy well-perfused skin.42,43 Diller44
`further calculated that 3 to 28 hours of exposure to
`a heating pad at 40°C would be required for a first-
`degree burn. Importantly, the threshold for thermal
`injury has not been determined for thin or poorly per-
`fused skin.42
`
`Although heating pads are generally considered safe
`when used appropriately by individuals with normal
`functioning vasomotor and neurosensory function, the
`need for caution should be appreciated, especially for
`those who may be more susceptible to thermal
`injury.32,40,46–51 The use of heating pads is contra-
`indicated in persons who have a reduced sensitivity
`heat or impaired sensory and vasomotor function,
`including patients with diabetes, peripheral vascular
`disease, or any condition of sensory loss.40,46–51 Heat-
`ing pads that have been tested by UL ensure engi-
`neering standards and safety testing and should be used
`in accordance with detailed warning labels.44 Specifi-
`cally, practices of prolonged use, local compression, or
`lack of insulating covering should be strictly avoided.
`
`clearance on the distal extremities after a single treatment
`to a level that is similar to published data for the head and
`facial skin.8,9,20 Warming the skin within the threshold
`of thermal tolerability was well tolerated by subjects,
`despite moderate increases in stinging during light
`exposure and increased PDT skin reactions after
`treatment. A long-term follow-up study is currently
`underway to evaluate the longevity of AK clearance.
`The results of this study suggest that the potential for
`local skin warming to enhance cutaneous PDT for other
`indications may also be promising. At the least, these
`data should bring awareness to the clinical relevance of
`ambient temperatures during the incubation of por-
`phyrins used for cutaneous PDT for all indications.
`
`Limitations
`
`The temperatures reported are likely slightly lower
`than the actual skin temperature because of the rapid
`loss of heat when the heating pad is lifted to obtain the
`reading and are limited by the precision of the infrared
`thermometer (62°C). The reliability of infrared
`thermometers for the measurement of skin temper-
`atures has been demonstrated.52,53 However, because
`of heat dissipation during temperature measurement
`and the potential interference of the plastic wrap, the
`use of a thermocouple applied directly to the skin
`surface under the plastic wrap and heat pad is rec-
`ommended for greater accuracy in future studies.
`
`Blinded photographic analysis comparing differences in
`the area of skin affected by visible AKs at 1 week
`compared with baseline was consistent with an
`increased PDT reaction on the heated side compared
`with controls. When comparing baseline photographs
`with 2 and 6 months, global differences were significant
`only at the 2-month time point. However, the decrease
`in lesion counts remained significant throughout the
`study period. This finding is likely due to the inadequate
`sensitivity of the global assessment analysis in subjects
`with low numbers of AK lesions, which affect a small
`area compared with the entire treatment area.
`
`References
`
`This study demonstrates that moderately increasing the
`skin temperature during the incubation of ALA enhances
`the PDT reaction in skin and increases the efficacy of AK
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`D E R M A T O L O G I C S U R G E R Y
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