Opinion
EDITORIAL
Photodynamic Therapy in Daylight for Actinic Keratoses
Hans Christian Wulf, MD, DMSc, PharmD
In conventional photodynamic therapy (PDT) for the treat-
ment of actinic keratoses (AK), 5-aminolevulinic acid (ALA) or
methyl aminolevulinate (MAL) is applied to the skin after gentle
curettage and stays there for a defined period of time (often
3 hours) to ensure accumula-
tion of protoporphyrin IX
Related article
(PpIX).1 During this time the
treated area must be covered against light by a bandage. After
the PpIX accumulation, certified lamps are used for a short il-
lumination of the photosensitized skin to activate PpIX.2,3 In
this process PpIX loses its activity and fluorescence property.
The emission spectrum of the lamps must cover wavelengths
that are absorbed by PpIX to a high degree, and absorbed by
other skin components to a low degree. This is done to en-
sure skin penetration, especially when treating thicker le-
sions. The absorption peaks of PpIX are found around 412, 509,
544, 582, and 635 nm, mainly in the blue, green, and red parts
of the spectrum.4 Conventional PDT is often associated with
pain and inflammation, and PDT with daylight as the activat-
ing light source, “daylight PDT,” was invented to overcome
some of these problems.5
The expression “daylight PDT” implies that the conven-
tional light source has simply been replaced by daylight. This,
however, is not the most important change in the methodol-
ogy. The fundamental change is that PpIX is activated continu-
ously by daylight exposure from about 30 minutes after MAL
application, when PpIX starts forming in the skin (Figure).5 Il-
lumination must then be performed continuously for 2 hours.6
The treated area does not have to be protected from light at any
time. With this procedure there is no build-up of PpIX because
it is inactivated as quickly as it is formed (Figure). During the
first half hour the patients may be outdoors, indoors, or driv-
ing home, but should then be outdoors during the following 2
hours of daylight illumination, eg, in their own garden. The ad-
PpIX Fluorescence, AU
vantage of this PDT procedure is that it is practically painless,
as opposed to conventional PDT, while it also reduces posttreat-
ment inflammation to some degree.7 Inflammation causes ery-
thema, discomfort, and irritation of the skin for days after treat-
ment, and often results in downtime away from work.8 To
further reduce erythema the PDT treatment may be combined
with topical glucocorticosteroid without losing efficacy.9
In general, daylight PDT can be performed all year around
in countries south of latitude 45° north, which includes South-
ern Europe, South America, Australia, and most of the United
States. North of these geographical locations there are cer-
tain limitations due to low temperatures and low light inten-
sity, mainly from October to April.10 Temperatures below 10°C
will be too cold for elderly people with AK to endure, espe-
cially if it is also windy. This is particularly relevant if the AKs
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are located in areas of skin normally covered by clothes. Rainy
days in particular represent a challenge all year round, mak-
ing scheduling of patient treatment difficult in clinics. When
rain or windy weather makes it unpleasant to be outdoors, an
alternative is daylight illumination in a greenhouse.
Daylight fluence rate will fluctuate a good deal over the day
depending on the sun’s angle and cloud cover. It is important
to have sufficient intensity to prevent accumulation of PpIX
at the end of illumination. If skin PpIX fluorescence measure-
ments are performed at the end of treatment outdoors or in a
greenhouse, it is possible to establish the minimum daylight
fluence rate necessary to ensure total PpIX activation. If PpIX
fluorescence has not totally disappeared at the end of illumi-
nation the full effect of PDT has not been reached because not
all PpIX has been activated.11
Patients with AK are generally advised to use sun protec-
tion and limit their sun exposure, and may therefore find it dif-
ficult to understand that they are now being asked to remain
outdoors for 2 hours, though not necessarily in direct sun-
light. Two hours outdoors will, in many locations, result in a
sunburn and daylight PDT is thus preceded by sunscreen ap-
plication by the clinician.12 The sunscreen must not contain
physical UV filters such as titanium dioxide or zinc oxide as
these reduce the penetration of light which activates PpIX.
If the treatment takes place in a greenhouse, the glass will
absorb most of the UVR wavelengths that can provoke ery-
thema, and sunscreen pretreatment may thus be omitted.
Figure. PpIX Fluorescence Increase in Conventional PDT and
Daylight PDT
50
Conventional PDT
40
Daylight PDT
30
20
10
0
0 1 2 3
Time, h
The upper curve illustrates protoporphyrin IX (PpIX) in skin covered from light
and the lower curve illustrates a small PpIX formation half an hour after methyl
aminolevulinate (MAL) application and no accumulation at all during the
following 2 hours of daylight photodynamic therapy (PDT). AU indicates
arbitrary units; pdt, photodynamic therapy; PpIX, protoporphyrin IX.
(Reprinted) JAMA Dermatology Published online February 3, 2016 E1
 Opinion Editorial

After daylight exposure, excess MAL/ALA is removed and
the patients must avoid outdoor light for the rest of the day.
This means staying indoors or, if the patients go outside, cov-
ering the skin with clothes, wearing a hat, and applying a physi-
cal sunscreen to protect exposed skin.13
Daylight PDT does not require direct sunshine on the le-
sion area, and ambient radiation from the sky without direct
sunlight is effective. In this case light is coming from all direc-
tions, and the fluence rate may be more stable when people
change position than in direct sunlight, where the angle of di-
rect sunlight to the treatment field probably follows a cosine
response. The light intensity outside or in a greenhouse at the
end of treatment will nearly always be sufficient and gener-
ally there will be no need for measuring the fluence rate.
The drawbacks of daylight PDT mentioned above call for al-
ternativestodaylightwhilemaintainingthe2-hourexposuretime.
In this issue of JAMA Dermatology, O’Gorman et al14 present a
clinical study in which operating room LED light is used for in-
door “daylight PDT,” illustrating that this type of lamp constitutes
an alternative to daylight. Their proposed treatment can be per-
formed all year round, and since most clinics already have oper-
ating room lamps there is no extra cost for special lamps. How-
ever, treatment of the patients with this type of lamp will require
space. Other types of lamps that may be usable for “daylight PDT”
are slide projectors, overhead projectors, and blue or red LED
lamps (Actilite), which are also used in conventional PDT.11,15
For PDT to be effective with an artificial light source cer-
tain criteria have to be met. Figure shows that more and more
PpIX accumulates in the skin over time during conventional
PDT until illumination starts, typically after 3 hours. In day-
light PDT no accumulation of PpIX takes place. To achieve this,
the light fluence rate must be sufficient to activate all PpIX
within the 2 hours of illumination.11 Maximal effect needs more
than 4 to 8 J/cm2 PpIX weighted daylight for maximum cure
of AK.12 However, if the fluence rate has to be controlled it can
be done very inexpensively by using a Luxmeter. Lux is a sur-
rogate measure that can be performed very affordably and
without special skills.A lux measurement of 5000 seems to be
needed in order to obtain maximal effect of daylight PDT on
the AK cure rate.11 This is very little and can be encountered
on nearly all days of the year when it is convenient to stay out-
doors. The Lux is typically over 100 000 on a sunny day.
Different artificial light sources will have different emis-
sion spectra, which results in differences in the absorbed light
in PpIX, and different light sources will thus have to have dif-
ferent fluence rates to acheive the same efficacy. The light from
lamps can be aimed directly at the lesion area and has a rela-
tively stable fluence rate. The treatment can thus be per-
formed in a controlled manner, in contrast to treatment in day-
light, which nearly always fluctuates in fluence rate, not only
over the day but also because of varying cloud cover.
Daylight PDT is very popular among patients with AK and
most patients decline treatment with conventional PDT after
having experienced this changed treatment modality with few
adverse effects.7 Another consequence of daylight PDT is that
the patients wish to have much larger areas of skin treated each
time they visit the clinic.
It is very easy for dermatologists to gain experience with
this new daylight PDT modality, which can be performed with-
out buying special light equipment. It is uncomplicated and
advantageous for the clinic and at the same time preferred by
patients.

ARTICLE INFORMATION
Author Affiliation: Department of Dermatology,
Bispebjerg Hospital, University of Copenhagen,
Denmark.
Corresponding Author: Hans Christian Wulf, MD,
DMSc, PharmD, Professor, Department of
Dermatology, D42, Bispebjerg Hospital, University
of Copenhagen, Bispebjerg Bakke 23, DK-2400
Copenhagen NV, Denmark (h.wulf@regionh.dk).
Published Online: February 3, 2016.
doi:10.1001/jamadermatol.2015.5979.
Conflict of Interest Disclosures: Dr Wulf has
received speaking, traveling, and research grants
from Galderma.
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