Opinion

EDITORIAL

Photodynamic Therapy in Daylight for Actinic Keratoses

Hans Christian Wulf, MD, DMSc, PharmD

jamadermatology.com

are located in areas of skin normally covered by clothes. Rainy

days in particular represent a challenge all year round, making 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 suns 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 measurements 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 illumination 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 protection and limit their sun exposure, and may therefore find it difficult to understand that they are now being asked to remain
outdoors for 2 hours, though not necessarily in direct sunlight. Two hours outdoors will, in many locations, result in a
sunburn and daylight PDT is thus preceded by sunscreen application 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 erythema, and sunscreen pretreatment may thus be omitted.
Figure. PpIX Fluorescence Increase in Conventional PDT and
Daylight PDT
50
Conventional PDT
Daylight PDT

40

PpIX Fluorescence, AU

In conventional photodynamic therapy (PDT) for the treatment 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 accumulation 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 illumination 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 ensure skin penetration, especially when treating thicker lesions. 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 activating light source, daylight PDT, was invented to overcome
some of these problems.5
The expression daylight PDT implies that the conventional light source has simply been replaced by daylight. This,
however, is not the most important change in the methodology. The fundamental change is that PpIX is activated continuously by daylight exposure from about 30 minutes after MAL
application, when PpIX starts forming in the skin (Figure).5 Illumination 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 driving home, but should then be outdoors during the following 2
hours of daylight illumination, eg, in their own garden. The advantage of this PDT procedure is that it is practically painless,
as opposed to conventional PDT, while it also reduces posttreatment inflammation to some degree.7 Inflammation causes erythema, discomfort, and irritation of the skin for days after treatment, 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 Southern Europe, South America, Australia, and most of the United
States. North of these geographical locations there are certain limitations due to low temperatures and low light intensity, mainly from October to April.10 Temperatures below 10C
will be too cold for elderly people with AK to endure, especially if it is also windy. This is particularly relevant if the AKs

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20

10

0
0

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

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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, covering the skin with clothes, wearing a hat, and applying a physical sunscreen to protect exposed skin.13
Daylight PDT does not require direct sunshine on the lesion area, and ambient radiation from the sky without direct
sunlight is effective. In this case light is coming from all directions, and the fluence rate may be more stable when people
change position than in direct sunlight, where the angle of direct 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 generally there will be no need for measuring the fluence rate.
The drawbacks of daylight PDT mentioned above call for alternativestodaylightwhilemaintainingthe2-hourexposuretime.
In this issue of JAMA Dermatology, OGorman et al14 present a
clinical study in which operating room LED light is used for indoor daylight PDT, illustrating that this type of lamp constitutes
an alternative to daylight. Their proposed treatment can be performed all year round, and since most clinics already have operating room lamps there is no extra cost for special lamps. However, 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 certain 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 daylight PDT no accumulation of PpIX takes place. To achieve this,
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.
REFERENCES
1. Peng Q, Moan J, Warloe T, et al. Build-up of
esterified aminolevulinic-acid-derivative-induced
porphyrin fluorescence in normal mouse skin.
J Photochem Photobiol B. 1996;34(1):95-96.
2. Szeimies RM, Karrer S, Radakovic-Fijan S, et al.
Photodynamic therapy using topical methyl
5-aminolevulinate compared with cryotherapy for
actinic keratosis: A prospective, randomized study.
J Am Acad Dermatol. 2002;47(2):258-262.
3. Kennedy JC, Pottier RH, Pross DC.
Photodynamic therapy with endogenous
protoporphyrin IX: basic principles and present
clinical experience. J Photochem Photobiol B. 1990;
6(1-2):143-148.
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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 surrogate 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 outdoors. The Lux is typically over 100 000 on a sunny day.
Different artificial light sources will have different emission spectra, which results in differences in the absorbed light
in PpIX, and different light sources will thus have to have different fluence rates to acheive the same efficacy. The light from
lamps can be aimed directly at the lesion area and has a relatively stable fluence rate. The treatment can thus be performed in a controlled manner, in contrast to treatment in daylight, 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 without buying special light equipment. It is uncomplicated and
advantageous for the clinic and at the same time preferred by
patients.

4. Peng Q, Warloe T, Berg K, et al. 5-Aminolevulinic

acid-based photodynamic therapy. Clinical research
and future challenges. Cancer. 1997;79(12):2282-2308.
5. Wiegell SR, Haedersdal M, Philipsen PA, Eriksen
P, Enk CD, Wulf HC. Continuous activation of PpIX
by daylight is as effective as and less painful than
conventional photodynamic therapy for actinic
keratoses; a randomized, controlled, single-blinded
study. Br J Dermatol. 2008;158(4):740-746.
6. Wiegell SR, Fabricius S, Stender IM, et al. A
randomized, multicentre study of directed daylight
exposure times of 1 vs. 2 h in daylight-mediated
photodynamic therapy with methyl
aminolaevulinate in patients with multiple thin
actinic keratoses of the face and scalp. Br J Dermatol.
2011;164(5):1083-1090.
7. Rubel DM, Spelman L, Murell DF, et al. Daylight
photodynamic therapy with methyl aminolevulinate
cream as a convenient, similarly effective, nearly
painless alternative to conventional photodynamic
therapy in actinic keratosis treatment: a randomized
controlled trial. Br J Dermatol. 2014;171(5):1164-1171.

therapy for actinic keratoses: a randomized clinical

trial. Br J Dermatol. 2014;171(6):1487-1492.
10. Wiegell SR, Fabricius S, Heydenreich J, et al.
Weather conditions and daylight-mediated
photodynamic therapy: protoporphyrin IX-weighted
daylight doses measured in six geographical
locations. Br J Dermatol. 2013;168(1):186-191.
11. Wiegell SR, Heydenreich J, Fabricius S, Wulf HC.
Continuous ultra-low-intensity artificial daylight is
not as effective as red LED light in photodynamic
therapy of multiple actinic keratoses. Photodermatol
Photoimmunol Photomed. 2011;27(6):280-285.
12. Wiegell SR, Haedersdal M, Eriksen P, Wulf HC.
Photodynamic therapy of actinic keratoses with 8%
and 16% methyl aminolaevulinate and home-based
daylight exposure: a double-blinded randomized
clinical trial. Br J Dermatol. 2009;160(6):1308-1314.
13. Petersen B, Wiegell SR, Wulf HC. Light
protection of the skin after photodynamic therapy
reduces inflammation: an unblinded randomized
controlled study. Br J Dermatol. 2014;171(1):175-178.

8. Wiegell SR, Wulf HC. Photodynamic therapy of

acne vulgaris using 5-aminolevulinic acid versus
methyl aminolevulinate. J Am Acad Dermatol.
2006;54(4):647-651.

14. OGorman SM, Clowry J, Manley M, et al.

Artificial white light vs daylight photodynamic
therapy for actinic keratoses: a randomized clinical
trial [published online February 3, 2016]. JAMA
Dermatol. doi:10.1001/jamadermatol.2015.5436

9. Wiegell SR, Petersen B, Wulf HC. Topical

corticosteroid reduces inflammation without
compromising the efficacy of photodynamic

15. Stender IM, Wulf HC. Photodynamic therapy

with 5-aminolevulinic acid in the treatment of
actinic cheilitis. Br J Dermatol. 1996;135(3):454-456.

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