Am J Clin Dermatol

https://doi.org/10.1007/s40257-018-0360-y

REVIEW ARTICLE

Daylight Photodynamic Therapy for Actinic Keratoses

Colin A. Morton1 • Lasse R. Braathen2

Ó Springer International Publishing AG, part of Springer Nature 2018

Abstract Topical photodynamic therapy (PDT) using in situ), superficial and certain thin basal cell carcinomas
daylight is effective in the treatment of actinic keratoses (BCCs), and AKs. The evidence for the use of DL-PDT
(AKs), offering the potential for treatment of large fields beyond AK is limited, although has been reported in actinic
such as full face and balding scalp, but with minimal cheilitis, superficial BCC, and acne and cutaneous leish-
therapy-associated pain. Comparison with conventional maniasis. There is emerging interest in combination ther-
PDT indicates similar efficacy for thin and moderate- apy for AK, using one or more field therapies such as DL-
thickness AKs, but with significantly less discomfort/pain, PDT as an option to complement with localized treatment
driving a patient preference for daylight-mediated PDT for residual lesions. We review current recommendations
(DL-PDT) compared with conventional PDT using high- and consider the appropriate place for DL-PDT in our
intensity office/hospital-based light sources. Treatment treatment armamentarium.
protocol involves the application of a photosensitizing
agent without occlusion and subsequent exposure to
ambient daylight within 30 min, with patients exposed to
Key Points
daylight for 1.5–2.0 h. Pivotal randomized controlled trials
in Europe and Australia have confirmed the efficacy of
Daylight photodynamic therapy (DL-PDT) is an
methyl aminolevulinic acid (MAL) DL-PDT in comparison
effective alternative to conventional PDT, with
with conventional MAL-PDT for mild and moderate-
equivalent efficacy for thin and moderate-thickness
thickness lesions on the face and scalp. Initial clearance
actinic keratoses (AKs) on the face and scalp.
rates of 70–89% are reported. DL-PDT using a
nanoemulsion aminolevulinic acid (ALA) has recently Tolerance of DL-PDT is high, with minimal or no
been shown to be at least as effective as MAL DL-PDT in treatment-associated pain.
treating mild and moderate-thickness AKs. DL-PDT may DL-PDT is especially suitable for patients with
offer a better-tolerated method for treating patients with multiple clustered AKs and field disease, and has
extensive AK disease. There is emerging literature on the additional potential in delaying/preventing new
potential for field PDT to reduce the number of new AKs lesion development.
developing, potentially preventing/slowing skin cancer
development. Conventional PDT remains established as a
therapy for Bowen’s disease (squamous cell carcinoma

& Colin A. Morton 1 Introduction

[email protected]
1
Department of Dermatology, Stirling Community Hospital, Photodynamic therapy (PDT) involves the activation of a
Stirling FK8 2AU, UK photosensitizing drug by visible light to produce activated
2
Dermatology, Bern, Switzerland oxygen species within target cells, resulting in their
 C. A. Morton, L. R. Braathen

destruction. Strong evidence is identified in therapy Europe, most clinical applications of PDT have used red
guidelines to indicate that topical PDT is effective for light around 630–635 nm to achieve adequate penetration,
actinic keratoses (AKs), Bowen’s disease (squamous cell although, in the US, blue light that activates the 410 nm
carcinoma [SCC] in situ), superficial basal cell carcinomas peak is commonly used when treating thin/moderate-
(BCCs) and thin nodular BCCs [1–4]. thickness AKs [1–3].
Three photosensitizing agents are licensed and mar- Topical PDT offers the potential of a practical, non-
keted, but availability differs by country: a formulation of surgical, clinic/office therapy. PDT may prove advanta-
5-aminolevulinic acid (5-ALA; LevulanÒ, DUSA Phar- geous where large size, site, or number of lesions limit the
maceuticals, Wilmington, MA, USA), for AKs; a efficacy and/or acceptability of conventional therapies
nanoemulsion formulation of 5-ALA (AmeluzÒ, [1–4]. Fluorescence emitted following conversion of
(Biofrontera Pharma, Leverkusen, Germany) for AKs, absorbed ALA to the endogenous photosensitizer PpIX can
including field cancerization and superficial and/or nodular be visualized to assist delineation of surface tumour mar-
BCC; and an esterified formulation, methyl aminolevuli- gins or recurrent disease, and offers particular advantages
nate (MAL; MetvixÒ/MetvixiaÒ, Galderma, Paris, France), in using conventional PDT where extent of disease is
for AKs, Bowen’s disease, and superficial and nodular uncertain [7]. However, discomfort/pain is a common
BCC. LevulanÒ was approved by the US FDA in 1999 for adverse effect with conventional red-light PDT, especially
the treatment of AKs on the face/scalp. Although the label where larger lesions/fields are to be treated [2, 8].
states a 14- to 18-h interval between application and illu- Topical PDT using natural daylight is associated with
mination, in practice, 1 h short-contact, full-face therapy minimal discomfort, and evidence reviewed below indi-
has been shown to be as efficacious as longer incubation cates it to be as effective as conventional PDT in AK.
[5]. MetvixiaÒ (MAL hydrochloride) was approved by the Patients expose sites for treatment within 30 min of pho-
FDA in 2004 for the treatment of thin and moderately thick tosensitizer application, without occlusion, to daylight for
AKs of the face and scalp by conventional PDT but was 2 h [9]. During conventional red-light PDT, PpIX accu-
withdrawn in 2012 for commercial reasons (FDA label mulates during the 3-h occlusion, resulting in a high con-
only). centration of reactive oxygen species immediately
Topical PDT using daylight has more recently been following illumination, the primary cause of significantly
approved with licence extensions for Metvix/Metvixia in greater pain than during DL-PDT, when exposure to day-
Europe, Australia, Canada and Latin America, and in light commences within 30 min after MAL application,
March 2018 the European Medicines Agency approved just after initial synthesis of PpIX, permitting constant
daylight DT using AmeluzÒ (nanoemulsion aminolevulinic photobleaching which results in almost no pain [2, 9].
acid hydrochloride) gel to treat AKs and field cancerizaton Although all PpIX absorption peaks are within the visible
5-ALA is a precursor in the heme biosynthesis pathway spectrum, 87% of daylight PpIX activation is due to blue
of protoporphyrin IX (PpIX), an endogenous photosensi- light (380–495 nm).
tizer not normally present within tissue in therapeutically In this review, the protocol for DL-PDT is assessed,
useful concentrations. Exogenous administration of each results of studies reviewed, and the potential place of DL-
5-ALA/MAL formulation increases the intracellular con- PDT in practice is considered.
centration of PpIX. The rationale for PDT is based on the
cytotoxic action of products generated by excited photo-
sensitizers, including singlet oxygen, which is highly 2 Treatment Protocol
reactive in biological systems [6]. For ALA/MAL-PDT,
inhibition of mitochondrial enzymes is likely to be the key DL-PDT is indicated for patients with grade I or II AKs, or
event in PDT cell death. fields of actinic damage on the face and scalp. A chemical
The development of energy-efficient LEDs has facili- sunscreen with a sun protection factor (SPF) C 20 should
tated the production of large area, yet portable, red-light be used to block UV, hence preventing sunburn during the
sources, which have become the most frequently used 2 h of daylight exposure, but products containing physical
lights in clinical practice for delivering PDT for all its filters such as zinc or iron oxide or titanium dioxide must
indications by standard conventional protocol, although a not be used [9]. No interaction between photosensitizing
blue-light source is approved for the treatment of AKs by agent and sunscreen has been shown [10].
LevulanÒ 5-ALA [1–3]. Light of appropriate wavelength Sunscreen application is recommended 15 min before
for activation of the photosensitizer is required in the target skin preparation, although lesion identification can be
tissue. 5-ALA-induced photosensitivity has a porphyrin- easier if it is left until after preparation. Sunscreen must be
like spectrum with maximum excitation at 410 nm and applied on all areas that will be exposed to the sun. Scales
additional smaller peaks at 510, 545, 580 and 635 nm. In and crusts can be removed and skin surface roughened to
Daylight PDT for Actinic Keratoses

enhance cream penetration using gentle curettage, mildly 2.1 Efficacy of Daylight Photodynamic Therapy
abrasive pads or microdermabrasion. Keratolytic pretreat- (PDT)
ment (salicylic acid or urea) is an alternative to curettage,
although it can also be associated with increased pain [11]. Conventional PDT with licensed formulations of 5-ALA,
Laser pretreatment might also be used to enhance cream nanoemulsion 5-ALA and MAL have been widely studied
delivery. for non-hyperkeratotic AKs of the face and scalp, with
For DL-PDT, MAL or nanoemulsion ALA should be typical clearance rates of 81–92% of lesions 3 months after
applied as a thin layer to the entire treatment field, without treatment [3, 4]. In a comparison of conventional protocols
occlusion, and daylight exposure should begin within using red light, PDT using the nanoemulsion gel formula-
30 min. Beyond this time, there is a risk of increased pain tion of ALA achieved patient complete clearance rates of
on initial light exposure. Two hours of daylight is recom- 78%, compared with 64% with MAL-PDT, when the
mended, with no benefit observed in longer exposure, but treatments were compared in a study of 600 patients, each
erythema may be greater [9]. The patient should remain with four to eight mild to moderate AKs on the face/scalp,
exposed to full daylight, avoiding dark shade, with similar in 26 European centres [17].
light intensity during the entire period of exposure. Con- Three initial trials of DL-PDT from the same centre
sideration of patient comfort is important on hot, cloudless cleared 79, 78, and 76% of AKs after a single treatment as
days, where shaded light is preferred and will reduce the investigators sought to refine the treatment protocol
sweating and sunburn. After daylight exposure, the cream [13, 18, 19]. In the first study, sunlight-mediated PDT was
should be washed off and the patient should cover the performed in a split-face protocol, where a 3-month
treatment area from sun for the rest of the day to reduce clearance rate of 79% was reported, compared with 71%
inflammation. The use of a topical corticosteroid can also for lesions treated with conventional red-light PDT [18]. In
be considered to reduce inflammation without affecting the second study, daylight, but not necessarily sunlight,
efficacy [12]. was used in a home-based setting, and 16 and 8% con-
DL-PDT can be performed in all weather conditions, centrations of MAL cream were also compared in a split
regardless of sun or cloud, but is not usually perfomed in face/scalp design [19]. At 3 months, 78% of lesions overall
rain, and, for patient comfort, should be undertaken where had cleared, with no difference between photosensitizing
the temperature is [ 10 °C [9]. Several studies have clo- agent concentrations but with a reduction in efficacy for
sely observed for the impact of light dose and weather grade II AKs (64%) and thick grade III AKs (39%) com-
conditions on the efficacy of DL-PDT, with implications pared with thin grade I lesions (80%). In the third study,
considered in a consensus review [9]. daylight exposure times of 1.5 versus 2.5 h were compared
Providing a threshold light dose is achieved, there is no and were shown to be equivalent, with 76% overall
association of lesion response with light dose or weather response of thin AKs in a multicentre, randomized trial
conditions, as demonstrated in a multicentre study in three [13]. Reduced efficacy of thicker lesions was demonstrated
Nordic countries [13]. in a trial, with 3-month clearance rates for types I, II, and
Although extensive use was made of electronic III AKs of 76%, 61% and 49%, respectively, after a single
dosimeters during clinical studies, both the observation of treatment of DL-PDT, with considerable variation in
lack of light dose-response correlation and subsequent response between centres [20].
meteorological modelling concluded that protocols for Two pivotal intraindividual multicentre comparative
delivery of PDT could be simplified as long as each centre studies were performed in a total of 231 patients in Aus-
considered whether local weather conditions restricted the tralia and Europe, both observing that MAL-PDT using
period of the year during which daylight PDT could be daylight was non-inferior to conventional PDT, with the
effectively performed. Australian study reporting lesion clearance rates of mild
Based on calculations of a PpIX light dose above 8 J/ AK of 89% and 93%, respectively, 12 weeks after one
cm2 and, for patient comfort, maximum temperature of at treatment session [21, 22]. The European study observed
least 10°C, in a study of six european locations it has been equivalent responses of 70% and 74%, with both values
demonstrated that DL-PDT can be performed most of the being lower as this study included patients with mild and
year, with the exception of the winter months in northern moderate-thickness lesions. Daylight PDT was virtually
countries, with data covering latitudes 20°N–70°N [14]. pain free in comparison with conventional PDT, and was as
Assessment of weather conditions confirmed the feasibility effective, whether performed in sunny or cloudy
for DL-PDT throughout the year in Central and South conditions.
America, as well as in Australia [15, 16]. Both high efficacy and patient satisfaction were
demonstrated in a further multicentre study conducted over
six European countries in 325 patients receiving a single
 C. A. Morton, L. R. Braathen

treatment of MAL DL-PDT for face and/or scalp AKs. This respectively, were observed during follow-up in another
study demonstrated efficacy at 3 months was at least much study, the 12-month clearance rate overall indicated a
improved in 83.5% of patients, with 45.9% of patients significantly high efficacy of conventional PDT versus DL-
requiring no retreatment. Moreover, the proportion of PDT of 76 and 66%, respectively [30]. Differences in
patients and physicians who were overall satisfied to very efficacy for this study, also predominantly of grade I AKs,
satisfied with the MAL DL-PDT treatment was 80.4 and were noted for lesions located on the face (scalp lesions
90.3%, respectively [23]. had equivalent clearance/recurrence rates). Despite the
Reflecting the need for suitable climate, several addi- better outcome of conventional PDT, almost 70% of AK I
tional trials have examined the efficacy of DL-PDT in lesions treated with DL-PDT were in complete remission at
specific countries, including Italy, Switzerland and Brazil. 12 months, with improved tolerability. The superior
In the study from Italy, where initial equivalent efficacy for clearance rate for scalp lesions compared with facial
AK type I was shown for DL-PDT (87%) and conventional lesions treated with DL-PDT may be due to more direct
PDT (91%), poorer efficacy was shown for type II (36 vs. exposure of bald scalp to daylight.
61% by conventional PDT) and type III (25 vs. 46% by
conventional PDT) AKs [24]. 2.3 Efficacy of Daylight-PDT for Actinic Keratoses
A retrospective study of DL-PDT in a private practice (AKs) in Immunosuppressed Patients
setting in Switzerland observed clearance of 77% of all
lesions, with most patients reporting no pain, along with Conventional ALA-PDT and MAL-PDT have both been
local skin reactions that settled within 10 days [25]. A shown to be effective in clearing AKs in organ transplant
strong patient preference for daylight over conventional recipients (OTRs). Although initial clinical response rates
PDT was expressed, with the one patient who experienced appear similar to those in immunocompetent patients, it has
pain having misunderstood instructions and remaining been noted that recurrence rates were higher in OTRs
indoors for 2.5 h before sitting out in the sun. during a 48-week follow-up [31]. Reduced efficacy of PDT
In a study of 14 patients from Sao Paulo, Brazil, DL- in OTRs may result from the large number of intraepithe-
PDT using MAL cleared 86% of AKs (grades I and II), lial lesions, more prominent hyperkeratosis, higher pro-
with no recurrences over 3 months [26]. Another small portion of lesions on sites, e.g. dorsum of hands, where
study demonstrated the efficacy and tolerability of DL- response rates are typically poorer, and an altered, sec-
PDT in a low-latitude city in Brazil, known for its intense ondary local immune response. Data comparing PDT with
sun, with 16/20 patients reporting no discomfort due to the other therapies in OTRs are limited, although MAL-PDT
procedure [27]. has been shown to be superior in efficacy to topical
In a randomized, split-face trial, 13 patients with 177 5-fluorouracil, even after 6 months, for the treatment of
grade I–III AKs received DL-PDT, with nanoemulsion epidermal dysplasia in OTRs [32].
ALA compared with MAL, with two treatments for grade DL-PDT using ablative fractional laser (AFL) resur-
II and III AKs [28]. Nanoemulsion ALA DL-PDT cleared facing pretreatment has been used to treat AKs in OTRs
85% of AKs, compared with 74% treated with MAL. The with the aim of overcoming the issues of poorer efficacy of
per patient half-face analysis showed ALA to have a sig- PDT in OTRs and treatment intolerance due to pain in
nificantly higher clearance rate for grade I AKs than MAL, conventional PDT [33]. In this randomized controlled trial
but, for thicker grades, clearance was equal. A recent (RCT), four areas were randomized in each patient. Three-
multicentre intraindividual comparison trial compared DL- month complete clearance rates for the patches treated
PDT using nanoemulsion ALA with MAL in 52 patients were superior with the pretreatment followed by DL-PDT,
with three to nine mild to moderate-thickness AKs on the with a median clearance rate of 74% compared with
face/scalp [29]. Equivalent efficacy was demonstrated at comparable complete clearance rates of 46% and 50% for
3 months, with total lesion clearance rates of 79.8% with DL-PDT and conventional PDT, respectively, without prior
AmeluzÒ and 76.5% with MetvixÒ formulations. treatment.

2.2 Long-Term Efficacy of Daylight-PDT

3 PDT for AK: Therapy Guideline
Data on sustainability of response to DL-PDT are limited Recommendations
beyond 12 weeks, although the multicentre Australian
study that treated only thin grade I AKs observed that 96% Guideline recommendations and systematic reviews to
of lesions responding at week 12 maintained complete inform treatment choice remain largely limited to publi-
response at 6 months [21]. Although similar recurrence cations reviewing conventional PDT. A Cochrane Library
rates of 13% and 10% for DL-PDT and conventional PDT, systematic review searched databases up to March 2011
Daylight PDT for Actinic Keratoses

and identified 83 RCTs that studied the effect of 18 topical 4 Use of Daylight PDT in Combination with Other
treatments for AK [34]. The primary outcome ‘participant Therapy
complete clearance’ significantly favoured field treatments
of 3% diclofenac in 2.5% hyaluronic acid, 0.5% 5-fluo- There is potential for combining PDT with other modalities
rouracil, 5% imiquimod, and 0.025–0.05% ingenol mebu- to improve efficacy or extend the reach of PDT. Data
tate, compared with vehicle or placebo. It significantly regarding combination use of DL-PDT are sparse, but
favoured the treatment of individual AK lesions with PDT pretreatment of AKs with topical 5-fluorouracil or
as early studies of PDT were designed towards individual diclofenac has been reported, as well as several combina-
lesion response. ALA-PDT was also significantly favoured tions of using topical imiquimod and conventional PDT
compared with cryotherapy. Based on investigator and [38]. A recent randomized intraindividual study investi-
participant evaluation, imiquimod treatment and PDT gated whether 7 days of pretreatment twice daily with
resulted in better cosmetic outcomes than cryotherapy and topical 5% 5-fluorouracil enhanced the treatment efficacy
5-fluorouracil. A more recent systematic review performed of DL-PDT in 24 patients with AKs on the hands [39]. At
in 2013 undertook to compare the evidence of the effec- 3-month follow-up, the overall lesion response rate was
tiveness of PDT compared with other therapies, restricted significantly higher for the combination (62.7 vs. 51.8%),
to RCTs with at least 10 participants [35]. Thirteen studies while pain and erythema were similar. Combination treat-
were included in the final analysis, of which four were ment could offer a very effective practical solution for
eligible for final meta-analysis. PDT was concluded to patients with extensive AK, including on limb sites, where
offer a 14% better chance of complete lesion clearance at we would anticipate a poorer efficacy with monotherapy.
3 months after treatment than cryotherapy for thin AKs on
the face and scalp.
Therapy-specific guidelines from the British Association 5 PDT: Evidence for Prevention of AK
of Dermatology list PDT alongside topical therapies as
suitable for isolated or scattered AKs, as a suitable choice Although the exact rate of malignant transformation to
for patients wishing to manage background actinic chan- SCC is unknown, the majority of SCCs appear to arise
ges, and as part of maintenance treatment for low-grade from within AKs [40]. Therapies that can treat large fields
AKs in sun-damaged skin [36]. In that evidence-based of actinically damaged skin may offer benefit in reducing
review, PDT is favoured where there are a large number of the development of new lesions and potentially new can-
AKs (field therapy) and for confluent recalcitrant AKs not cers, although there remains a lack of evidence of specific
responding to other treatments, with strong evidence for prevention of SCC to date. As a field-directed therapy,
use on the scalp and face. This will assist practitioners in PDT appears suitable for use for the treatment of areas of
deciding where best to deploy PDT within their clinical extensive actinic damage, offering the potential to treat
practice. subclinical lesions, and even potentially delay/prevent new
There is limited direct comparison evidence of DL-PDT lesions, with a decreased expression of p53 demonstrated.
with standard therapies. DL-PDT has been compared with The preventive potential of PDT has been studied in
ingenol mebutate in the treatment of 27 patients with 323 immunosuppressed (see below) and immunocompetent
grade I and II AKs. [37] Both 25 cm2 target areas achieved individuals; a single treatment of ALA-PDT demonstrated
complete response in 40.47% of cases, and the average AK a delay of approximately 6 months in the development of
lesion clearance rate was similar. Areas treated with DL- new AKs [41].
PDT had a lower reduction in mean grade II AK clearance Nanoemulsion ALA by either the conventional or,
rate compared with grade I AK, with reduction similar for recently, daylight protocol is licensed for the treatment of
both types in the ingenol-treated areas. The tolerability entire fields with cancerization (areas of skin where mul-
profile was superior for DL-PDT, with mean local skin tiple AK lesions are surrounded by an area of actinic and
responses and pain higher in areas treated with ingenol sun-induced damage within a limited field). Following a
mebutate. Reflecting on the excellent tolerability, there is a single treatment by the conventional protocol, nanoemul-
strong case for considering DL-PDT for large fields of sion ALA-PDT achieved a patient complete clearance rate
AKs, expecially where thin AKs are predominant, with a of 91% after a maximum of two treatments [42]. DL-PDT
balding scalp displaying multiple lesions particularly has been compared with conventional PDT as a preventive
appropriate for considering this modality. treatment for nonmelanoma skin cancer (NMSC) in
patients with actinic field damage [43]. Patients all had
previous NMSC on the face/scalp and AK on the same
fields. They received one cycle of treatment and were
 C. A. Morton, L. R. Braathen

evaluated for the development of new lesions over 1 year. An expert group met to develop recommendations for
The total number of new AKs and the mean time to the use of daylight MAL-PDT in patients with large-scale
development did not significantly differ between sides in photodamaged skin, and concluded that actinic field dam-
the 26 patients treated, but local adverse events were more age can be treated as effectively with daylight MAL-PDT
intense with conventional PDT. An open intrapatient ran- as conventional PDT, but with the advantage that treatment
domized study of 27 renal OTRs reported a significant is nearly pain free, facilitating its use over large areas of
delay in the development of new lesions at sites treated actinic field damage [55]. A recent parallel-group, double-
with conventional MAL-PDT [44]. By 12 months, 62% of blind, randomized placebo-controlled trial from Columbia
treated areas were free from new lesions, compared with assessed daylight MAL-PDT in 60 patients with facial
35% of control areas. In a further study of topical PDT in photodamage [56], and reported that treatment was well
81 OTRs, conventional MAL-PDT was administered twice, tolerated, without pain, and showed significant improve-
1 week apart, then at 3, 9 and 15 months [45]. Compared ment in photodamage, although Herpes simplex prophy-
with control sites, the occurrence of new lesions was laxis was recommended before sessions. A trial is currently
reduced during the initial months of the study, but lost by underway assessing the efficacy of repetitive DL-PDT in
27 months, suggesting additional treatments after preventing AK and investigating the possible rejuvenating
15 months might be required. effects of this treatment; results are awaited [57].
In a recent randomized split-face study to determine the DL-PDT using LevulanÒ has been used to treat 80
impact of field PDT on the development of new lesions, a patients from Southern California with multiple AKs
single treatment of conventional (lesional) MAL-PDT was related to chronic photodamage, with ALA applied 1 h
compared with PDT over the entire field in patients with a prior to light exposure, and with a chemical sunscreen
maximum of 10 AKs on each side (all lesions on the face or applied 30 min into incubation [58]. Patients sat outside for
scalp). After 9 months, significantly fewer new lesions 2.5 h and were requested to seek shaded or direct sunlight
were observed compared with the side receiving lesion- for 15–30 extra minutes the following day (after further
only therapy [46]. sunscreen application). They were advised to protect
An international consensus recommended PDT as a themselves from further sunlight and stay indoors for 48 h.
good therapy option to treat field cancerization, but rec- Patients tolerated treatment well, with no pain during the
ognized the tolerability issues of field treatment using first exposure, although patients described a mild burning
conventional PDT [47]. Reflecting on the superior tolera- sensation on the second day of exposure. Significant clin-
bility of DL-PDT over conventional PDT, prophylactic ical improvement was observed, with a reduction in AKs,
PDT using daylight in a 6-monthly cycle appears more as well as a reduction in lentigines and other signs of
feasible than by conventional protocol, but this requires ageing.
further study and consideration of cost effectiveness, as
well as comparison with other modalities.
7 Adverse Events

6 Daylight PDT for Photorejuvenation Guidelines indicate that the most common adverse event of
‘pain/discomfort’ restricted to the illuminated area, is
Several studies have reported on the rejuvenating effects of commonly experienced during PDT [1–4]. It usually peaks
PDT, such as reduced fine wrinkles, mottled hyperpig- within minutes of commencing light exposure and proba-
mentation, tactile roughness, skin texture, telangiectasias, bly reflects nerve stimulation and/or tissue damage by
facial erythema, and sallowness [48–51]. The cosmetic reactive oxygen species, possibly aggravated by hyper-
effects of topical PDT are supported by immunohisto- thermia. Although most patients will tolerate conventional
chemical analysis that showed both upregulation of colla- PDT without anaesthesia/analgesia, as the face and scalp
gen production and increased epidermal proliferation may be more susceptible to pain, there is strong interest in
[52, 53]. These molecular effects, together with the dis- refining the method of delivery of PDT so as to minimize
appearance of Tp53, a marker for epidermal carcinogene- pain and increase the scope for treatment of large fields,
sis, may explain why PDT is able to reverse the signs of e.g. face, balding scalp.
photoaging [54]. Chronically sun-damaged skin is also Several reports have tried to compare the pain associated
characterized by sallowness, telangiectasias, hyperpig- with conventional ALA and MAL-PDT, but differences in
mentations, roughness, and wrinkles. Therefore, simulta- disease indication, protocol and whether compounded or
neous treatment of AKs and photodamage is highly branded agents were used has limited direct comparison. In
desirable. a comparison of AKs treated with either conventional
ALA-PDT or MAL-PDT, less pain was associated with
Daylight PDT for Actinic Keratoses

MAL-PDT, but compounded ALA cream was utilized and were halogen, white light-emitting diode (LED), red LED
a longer drug incubation time period than standard US panel, and lamps used for conventional PDT. Four of the
therapy was used; comparison should be with 1-h drug five light sources were able to photobleach PpIX com-
incubation with LevulanÒ and 3-h drug incubation under pletely (intensity of light from red LED panel insufficient)
occlusion with MAL [59]. and offer an alternative light source for simulated daylight
Immediately following treatment, erythema and oedema PDT. The amount of PpIX activating daylight available in
were common, with erosion, crust formation and healing a glass greenhouse was also assessed as an alternative to
over 2–6 weeks, but ulceration is very rare. Swelling can daylight PDT, as originally described. The greenhouse was
be locally marked, giving rise to occasional observations of suitable for DL-PDT since the effect of solar light is
an urticated reaction at the treatment site. lowered by only 25%, and, as minimal UVB radiation
Hyper- or hypopigmentation can occasionally be seen in passes through the greenhouse glass, sun protection is not
treated areas but usually resolves within 6 months. Evi- needed.
dence would indicate the risk of cancer associated with Simulated daylight PDT has also been evaluated using
PDT to be low, but in view of the latent period for car- nanoemulsion ALA and paired illumination sources
cinogenesis, guidelines advise careful reporting of malig- installed at the ceiling of the treatment room, with patients
nancies in sites of prior PDT [1–4]. A few case reports are sitting in the room for 2 h after a short 30-min period of
noted in guidelines where skin cancer developed at sites occlusion of the ALA preparation [62]. The patient com-
where PDT had been performed, but these lesions may plete clearance rate 3 months after two sessions, 1 week
either represent evolution of a partially treated precancer apart, was 75% (82% in patients with only grade I lesions
by PDT, or the coincidental development of a skin cancer and 67% in patients with at least one grade II lesion), with
in a sun-damaged field receiving PDT to treat lesions a lesion clearance rate of 93%. Simulated DL-PDT is well
within the field. tolerated with no/minimal pain.
A study has compared the effectiveness of DL-PDT and
artificial white light (AWL) LED PDT for the treatment of
8 Cost Effectiveness of DL-PDT for AK AKs on the forehead and scalp [63]. DL-PDT involved
using MAL and standard protocol, while the AWL-medi-
Cost effectivenss of PDT delivered by different methods is ated MAL-PDT used an operating light source chosen for
hard to compare with multiple lesion and patient-specific the light spectrum of the LEDs. There was a 62% reduction
factors, as well as clinic set-up considerations. The cost in AKs after one treatment with DL-PDT and 68% for
effectiveness of DL-PDT compared with conventional PDT AWL-PDT at 1 month (48% and 64%, respectively, at
for AK was assessed in a ranndomized trial, with inclusion 9 months). Both treatments were rated highly tolerable by
of societal and private costs, including the time patients patients with no significant difference in pain scores.
spent in treatment [60]. The total costs per patient were
significantly lower for DL-PDT (€132) compared with
conventional PDT (€170), giving a cost saving of €38. The 10 Daylight PDT: Additional Indications
estimated probabilities for patients’ complete response
were 0.429 for DL-PDT and 0.686 for conventional PDT, a The concepts of daylight PDT have stimulated fresh
difference in probability of being healed of 0.257. The interest in the therapeutic scope of this therapy for der-
incremental cost-effectiveness ratio showed a monetary matological indications. Patients with lower-lip actinic
gain of €147 per unit of effectiveness lost. DL-PDT was cheilitis have been treated with DL-PDT, receiving two
therefore less costly but also less effective than conven- treatments 7–14 days apart [64]. Complete clinical
tional PDT, providing lower value for money. Further response was achieved in 7/10 patients at 3 months. A pilot
studies are required and the improved tolerance of DL-PDT study of previously untreated superficial and small nodular
should be recalled, as well as the cost impact of different BCCs using two DL-PDT treatments, 1 week apart, cleared
clinic set-ups for delivery of DL-PDT. 94% of lesions at 3 months, dropping to 74% complete
response at 12 months [65].
Daylight PDT using a novel variant of 5-aminolevuli-
9 Simulated Alternatives to Daylight PDT nate ester, 1.5% 3-butenyl ALA-bu gel, was used to treat
facial acne in a placebo-controlled trial [66]. At 12 weeks,
As climatic conditions may not always permit daylight both inflammatory and non-inflammatory acne lesions had
PDT outdoors, the spectrum of five different lamps for decreased significantly by 58.0% and 34.1%, respectively,
simulated indoor ‘daylight PDT’ were investigated for their in the PDT group.
ability to photobleach PpIX [61]. The lamps investigated
 C. A. Morton, L. R. Braathen

Cutaneous leishmaniasis (CL) has been shown to 3. Morton CA, Szeimies RM, Sidoroff A, Braathen LR. European
respond to DL-PDT, in an open study of 31 patients with guidelines for topical photodynamic therapy part 1: treatment
delivery and current indications—actinic keratoses, Bowen’s
CL, with patients either treated in the hospital garden under disease, basal cell carcinoma. J Eur Acad Dermatol Venereol.
supervision or at home [67]. The overall cure rate was 2013;27:536–44.
89%, and was similar between the hospital and home 4. Morton C, Szeimies RM, Sidoroff A, Wennberg AM, Basset-
treatment groups, increasing the ease of use of DL-PDT, Seguin N, Calzavara-Pinton P, et al. European Dermatology
Forum European Dermatology Forum Guidelines on topical
even in technologically deprived countries where the photodynamic therapy. Eur J Dermatol. 2015;25:296–311.
majority of Leishmania infections are encountered. 5. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A
trial of short incubation, broad-area photodynamic therapy for
facial actinic keratoses and diffuse photodamage. Arch Dermatol.
2004;140(1):33–40.
11 Conclusion 6. Kim M, Jung HY, Park HJ. Topical PDT in the treatment of
benign skin diseases: principles and new applications. Int J Mol
DL-PDT has a substantial evidence base, demonstrating Sci. 2015;16:23259–78.
equivalence to conventional PDT, although efficacy for 7. Fritsch C, Lang K, Schulte KW, Neuse W, Ruzicka T, Lehman P.
Fluorescence diagnosis and photodynamic therapy in dermatol-
thicker AKs may be inferior to alternative therapies. ogy: an overview. In: Patrice T, editor. photodynamic therapy.
Consensus recommendations from national experts have Cambridge: Royal Society of Chemistry; 2003. p. 177–212.
concluded that DL-PDT has a role in the treatment of AKs 8. Grapengiesser S, Ericson M, Gudmundsson F, Larkö O, Rosén A,
in Australia, South America, and Europe, including the UK Wennberg AM. Pain caused by photodynamic therapy of skin
cancer. Clin Exp Dermatol. 2002;27:493–7.
and the Iberian peninsula [68–72]. The absence or near 9. Wiegell SR, Wulf HC, Szeimies RM, Basset-Seguin N, Bisson-
absence of pain during treatment has overcome the prin- nette R, Gerritsen MJ, et al. Daylight photodynamic therapy for
cipal concern about using topical PDT over larger areas. actinic keratosis: an international consensus: International Soci-
The opportunity for field DL-PDT to the face or scalp is ety for Photodynamic Therapy in Dermatology. J Eur Acad
Dermatol Venereol. 2012;26:673–9.
practical and can reduce costs associated with delivery of 10. Osman-Ponchet H, Sevin K, Gaborit A. Lack of effect of selected
the treatment. There are restrictions on when PDT can be sunscreens applied on ex vivo human skin for 5-methyl-
administered in many countries, depending on climatic aminolevulinic acid penetration and protoporphyrin IX photoac-
considerations, but alternative light sources that simulate tivation. Photodiagnosis Photodyn Ther. 2017;17:75–81.
11. Gholam P, Fink C, Bosselmann I, Enk AH. Retrospective anal-
PDT are under study. Additional indications for DL-PDT ysis evaluating the effect of a keratolytic and physical pretreat-
are being explored and seek to extend the potential of PDT ment with salicylic acid, urea and curettage on the efficacy and
as a useful platform for the treatment of several der- safety of photodynamic therapy of actinic keratoses with
matoses. Additional data comparing DL-PDT with other methylaminolaevulinate. J Eur Acad Dermatol Venereol.
2016;30:619–23.
therapies for AK are required, along with relevant cost- 12. Wiegell SR, Petersen B, Wulf HC. Topical corticosteroid reduces
effectiveness assessment. Nevertheless, current evidence inflammation without compromising the efficacy of photody-
indicates DL-PDT to be an effective, well-tolerated therapy namic therapy for actinic keratoses: a randomized clinical trial.
where field treatment may reduce new lesion development, Br J Dermatol. 2014;171:1487–92.
13. Wiegell SR, Fabricius S, Stender IM, Berne B, Kroon S,
as well as offer photorejuvenation. Andersen BL, et al. A randomized, multicentre study of directed
daylight exposure times of 1(1/2) vs. 2(1/2) h in daylight-medi-
Compliance with Ethical Standards ated photodynamic therapy with methyl aminolaevulinate in
patients with multiple thin actinic keratoses of the face and scalp.
Funding No external funding was used in the preparation of this Br J Dermatol. 2011;164:1083–90.
manuscript 14. Wiegell SR, Fabricius S, Heydenreich J, Enk CD, Rosso S,
Bäumler W, et al. Weather conditions and daylight-mediated
Conflicts of interest Colin A. Morton has been a member of advi- photodynamic therapy: protoporphyrin IX-weighted daylight
sory boards for Almirall, Biofrontera, Galderma, and Leo Pharma, doses measured in six geographical locations. Br J Dermatol.
and has received speaker honoraria from Biofrontera and Galderma. 2013;168:186–91.
Lasse R. Braathen has received congress/travel support, and fees for 15. Grinblat B, Galimberti G, Pantoja G, et al. Feasibility of daylight-
lectures and advisory board participation from Galderma. mediated photodynamic therapy for actinic keratosis throughout
the year in Central and South America: a meteorological study.
Int J Dermatol. 2016;55:e488–93.
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