ARTICLE
Auteur(s) : Philipp
Babilas, Michael Landthaler, Rolf-Markus Szeimies
Department of Dermatology, University of Regensburg,
Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany
accepté le 23 Novembre 2005
Hermann von Tappeiner, director of the Institute of Pharmacology at
the University of Munich, already coined the term “photodynamic
reaction” 100 years ago. According to the observations of one of
his doctoral students, Oscar Raab, the reaction was characterised
as an oxygen dependent tissue reaction following photosensitization
and irradiation with light [1, 2]. Oscar Raab could show in his
experiments that acridine orange was lethal for paramecia in the
presence of sunlight [1]. The toxicity of acridin orange on
protozoae was not only dependent on the dye concentration, but also
on the intensity of the ambient light. Von Tappeiner successfully
treated, in cooperation with the dermatologist Jesionek, patients
with topical Eosin solution (1-5%) suffering from lupus vulgaris,
secondary syphilis and superficial skin cancer [2]. In 1911
Hausmann reported photodynamic effects on mice injected with
hematoporphyrin showing extensive edema and erythema after light
exposure. The German researchers, Auler and Banzer, observed in
1942 the specific uptake and retention of hematoporphyrin in tumors
with subsequent higher fluorescence in tumors as compared to
surrounding tissue. Following irradiation with a powerful quartz
lamp they were also able to demonstrate histologically widespread
necrosis [2]. Thereafter, PDT was forgotten until Dougherty
initiated a renaissance in the mid seventies by treating patients
with cutaneous and subcutaneous tumors following injection of the
photosensitizer dihematoporphyrin and light irradiation. The
majority of the tumors treated showed either complete or partial
remission [2-4]. Today, it is known that PDT requires precisely the
simultaneous presence of a photosensitizer, light and oxygen inside
the diseased tissue. The photosensitizer is accumulated in the
target cells and absorbs light of a certain wavelength. The energy
is transferred to oxygen and highly reactive oxygen species –
mainly singlet oxygen – are generated. Treating with appropriate
light doses, the reactive oxygen species directly lead to cell and
tissue damage by inducing necrosis and apoptosis and indirectly
stimulate inflammatory cell mediators. Following lower light doses
treating inflammatory dermatoses, immunomodulatory effects are
induced. In the past decades, PDT has gained worldwide popularity,
first as an experimental therapy for a variety of human cancers.
Mainly porphyrins, chlorine derivatives or phthalocyanines have
been studied so far, for primary or adjuvant cancer therapy [5].
However, for dermatological purposes, only hematoporphyrin
derivatives like porfimer sodium (Photofrin®) or
protoporphyrin IX (PpIX)-inducing precursors like 5-aminolevulinic
acid (ALA) or methyl aminolevulinate (MAL) are of practical
concern. As systemic photosensitizing drugs induce a prolonged
phototoxicity [6], topical photosensitizers are preferred for use
in dermatology. Meanwhile drugs like ALA or MAL have reached
approval status for epithelial cancers or their precursors
throughout the world and there is growing interest in the use of
PDT not only for non-melanoma skin cancer but also for other skin
tumors like lymphoma or for tumor surveillance in transplant
patients as well as for non-oncological indications [7-10].
Photosensitizers
Eosin red or erythrosine were the first dyes Georges Dreyer in
Copenhagen and Albert Jesionek in Munich used at the beginning of
the last century as topical “photosensitizers” to treat conditions
like syphilis, lupus vulgaris, pityriasis versicolor, psoriasis,
molluscum contagiosum or skin cancer [2]. However, due to
recurrence and severe side effects these experiments were
abandoned. Since 1908 the tumor localizing effects of porphyrins
have been studied. In the late 1970s, hematoporphyrin derivative
(HPD) based PDT for the treatment of skin cancer came up again
[2-4]. The main problem in the use of HPD is the prolonged skin
photosensitization which lasts for several weeks [11]. Topical
application is not possible since the rather big molecules
(tetrapyrrol rings) do not penetrate the skin. Therefore the
introduction of porphyrin precursors like ALA or later MAL by
Kennedy and co-workers in 1990 was a significant milestone in the
development of PDT in dermatology, as the small molecules easily
penetrate the epidermis due to their low molecular weight [2, 12].
In the USA the 5-ALA hydrochloride (Levulan® Kerastick),
is approved for photodynamic treatment of actinic keratoses in
combination with blue light [5]. The 5-ALA based photosensitisers
are not photoactive by themselves, but show a preferential
intracellular accumulation inside the altered cells constituting
the diseased tissue and are metabolized in the haem biosynthesis to
photosensitizing porphyrins rather selectively inside these cells
[2, 13]. If no surface illumination is given, the porphyrins are
metabolized to the photodynamically inactive haem within 24 to 48
hours.
Meso-tetrahydroxyphenylchlorin (mTHPC) or benzoporphyrin
derivative monoacid A ring (Verteporfin) are other photosensitizers
that have been applied systemically for the treatment of BCC and
Bowen’s disease [14, 15]. In contrast to HPD, these second
generation photosensitizers show only limited cutaneous
phototoxicity.
Light sources
Following formation of the photosensitizing porphyrins, they can be
activated by light of the appropriate wavelength. The porphyrins or
related photosensitizers with a tetrapyrrolic structure exhibit a
very typical absorption spectrum with the highest peak at
approximately 405 nm, the so called Soret-band. Besides, several
Q-bands exist, the last having an absorption peak at 635 nm.
Although the peak is much smaller than that at 405 nm, this
wavelength is preferentially used for irradiation since light in
the red spectrum shows the best tissue penetration [16, 17].
However, blue light (BLU-U, DUSA Pharmaceuticals, Florida, USA) is
approved in the USA in the combination with 5-ALA hydrochloride
(Levulan® Kerastick) for photodynamic treatment of
non-hyperceratotic actinic keratoses [5, 18]. In addition, white
light sources or green light sources also exist for PDT. However,
it has been demonstrated in a comparative trial that light at
shorter wavelengths is less effective in the treatment of Bowen’s
disease at a theoretically equivalent dose; therefore only the use
of red light is recommended for PDT of skin tumors [19, 20]. With
red light, non-melanoma skin cancer up to a thickness of
2-3 mm can be treated, thicker lesions require multiple
treatments or tissue preparation (debulking) prior to PDT [21-23].
For irradiation in PDT, lasers and incoherent light sources have
been used [24-27], Pulsed laser light sources matching one of the
Q-bands at 585 nm have been evaluated with equal results compared
to an incoherent light source in the treatment of AK [26]. Although
not ideally matching the porphyrin absorption spectrum, the use of
a long pulsed dye laser at 595 nm also seems to be effective for
the same indication [28]. However, incoherent light-sources exhibit
fundamentally different irradiation characteristics as compared to
lasers. As coherence is lost within less than a millimetre of
penetration into skin, this property is not mandatory for PDT [27].
Irradiation with incoherent light sources is more reliable,
simpler, and cheaper and usually shows similar efficacies as
compared to laser irradiation [29, 30]. Therefore, the gold
standard in topical PDT are incoherent light sources, either lamps
(e.g. PDT 1200L, Waldmann Medizintechnik, Germany) or LED’s (light
emitting diodes) (e.g. Aktilite™, Galderma, France; Omnilux PDT™,
Phototherapeutics, UK), which match the absorption maxima of the
ALA- or MAL-induced porphyrins and accomplish the simultaneous
irradiation of larger areas [17, 25, 30-32]. For tissue
destruction, treating malignant tumors, a light dose – using broad
spectrum red light (580-700 nm) – of 100-150 J cm–2
(100-200 mW cm–2) is chosen. For the more narrow
emission spectra of the LED systems (bandwidth approx. 30 nm) the
values are significantly lower (37-50 J cm–2). The light
intensity should not exceed 200 mW cm–2 to avoid
hyperthermic effects [17, 30]. For inflammatory dermatoses a light
dose of 10-40 J cm–2 and a light intensity of 50-70
mW cm–2 are sufficient (broad spectrum red light,
usually multiple treatments). During irradiation, both the patient
and clinic staff should be wearing protective goggles in order to
avoid the risk of eye damage [33].
Mechanism of action
In the presence of oxygen, the activation of a photosensitizer by
light of the appropriate wavelength leads to the generation of
reactive oxygen species (ROS), in particular singlet oxygen.
Depending on the amount and localization in the target tissue these
ROS modify either cellular functions or induce cell death by
necrosis or apoptosis [5, 10, 13]. There is a need for heme and
related molecules in fast proliferating, relatively iron-deficient
tumor cells of epithelial origin. Therefore intracellular uptake of
heme-precursors like ALA or MAL is eased, thus resulting in a
preferential sensitization of those cells. The same applies for the
target cells constituting inflammatory dermatoses. Therefore,
tissue damage is mostly restricted to the sensitized cells almost
omitting the surrounding tissue, especially cells of mesenchymal
origin like fibroblasts, resulting in an excellent cosmesis [20].
Aside from two case reports with possible coincidence, no further
reports on the carcinogenic potential of ALA/MAL-PDT have been
published [20]. Moreover, in a recent study even long-term topical
application of ALA and subsequent irradiation with blue light in a
hairless mouse model did not induce skin tumors [34]. Stender et
al. even showed a delay in photo-induced carcinogenesis in mice
following repetitive treatments with ALA-PDT [35].
Practical aspects of topical PDT
As it could be shown that hyperkeratosis is the reason for a poor
response to PDT of AKs localized on the hands [13], keratolysis
should be performed in hyperkeratotic lesions prior to incubation
with the aid of a gentle abrasion or a non-bleeding curettage [23,
32, 33, 36]. Overnight incubation with an ointment for easy
mechanical removal might also work. Extemporaneous ALA preparations
are mostly applied to the lesions with little overlap to the
surrounding tissue for 4-6 hours prior to irradiation under
occlusion and in addition with a light protective dressing or
clothing [13]. For the licensed MAL formulation
(Metvix®, Galderma, France) a shorter incubation time of
three hours is sufficient, due to preferential uptake and higher
selectivity [37, 38]. The entire area here is also covered with an
occlusive foil to allow for better penetration (table 1( Table 1 ); ( figure 1 )).
The most important side effects of PDT are stinging pain and a
burning sensation. Even if they are usually restricted to the time
span of irradiation and a couple of hours thereafter [20], they
often limit the patients’ compliance. Especially if an extended
irradiation field is selected, administration of analgesics is
often necessary [39]. Pain perception can also be alleviated by
concurrent cold air analgesia which improves the tolerability of
ALA/MAL-PDT [40]. Application of topical analgesics like eutectic
mixtures of lidocaine/prilocaine prior to irradiation interacting
with the incubation period of ALA/MAL are not recommended since
their high pH might chemically inactivate the photosensitizer.
Following tumor treatment, localized erythema and edema in the
treated area are usually seen, followed by a dry necrosis sharply
restricted to the tumor bearing areas over the next days. After
10-21 days, the crusts formed come off and, usually, complete
re-epithelialization is observed. During this phase, most patients
report only slight discomfort. Due to significantly lower doses of
both light and photosensitizer in the context of “low-dose-PDT”
treating inflammatory dermatoses, a few minor or no side-effects
are observed, although multiple treatments are necessary.
Due to the photosensitization, which is restricted to cells of
epithelial origin and does not sensitize fibroblasts or dermal
fibres, no scarring or ulceration is usually observed clinically
[13, 20, 22]. Pigmentary changes are also rare and only of
temporary duration. Irreversible alopecia has not yet been observed
in treated patients, however, due to the concomitant sensitization
of the pilosebaceous units this effect should be taken into account
[13, 20].
Apart from in patients with a known history of porphyrias or
allergic reactions to active ingredients of the applied
sensitizers, no severe limitations to performing ALA/MAL-PDT are
known [41]. PDT can be repeated several times and even in areas
with prior exposure to ionizing irradiation, PDT is possible
[42].
Table 1 Country-specific approval of topical MAL-
(Metvix®) or ALA- (Levulan® Kerastick) PDT
for the treatment of different oncologic and nononcologic diseases
(Y = yes; N = no). (as of 9/05)
|
Disease
|
Approval MAL (Europe, NZL, AUS)
|
Approval ALA (USA, CDN)
|
|
Oncologic Indications
|
|
|
|
Bowen’s Disease
|
Y
|
N
|
|
Actinic Keratosis
|
Y (also USA)
|
Y (in combination with blue light)
|
|
Squamous Cell Carcinoma
|
N
|
N
|
|
Basal Cell Carcinoma
|
Y
|
N
|
|
Nononcologic Indications
|
|
|
|
Psoriasis vulgaris
|
N
|
N
|
|
Vulgar warts
|
N
|
N
|
|
Genital warts
|
N
|
N
|
|
Acne vulgaris
|
N
|
N
|
|
Morphea
|
N
|
N
|
|
Lichen sclerosus
|
N
|
N
|
|
Actinic cheilitis
|
N
|
N
|
|
Nevus sebaceus
|
N
|
N
|
|
Epidermodysplasia verruciformis
|
N
|
N
|
Therapeutic applications – oncologic indications
Regarding oncologic indications, actinic keratoses (AK) and nodular
or superficial basal cell carcinomas are approved indications for
MAL. In addition, treatment of Bowen’s disease is also indicated
for PDT with ALA/MAL-induced porphyrins as recommended by evidence
based guidelines [20]. However, for therapy of single lesions,
several efficient alternative treatments are available, e.g.
cryotherapy or surgery, whereas for therapy of multiple lesions PDT
may be the first choice, in particular for actinic keratoses of the
scalp and face or in cases of basal cell nevus syndrome [5].
Actinic keratosis
Meanwhile, a number of registered chemical and/or immunological
treatment options exist for the treatment of actinic keratoses
(5-Fluorouracil, Podophyllin, Imiquimod, Diclofenac, PDT) [43]. The
efficacy of ALA-PDT has been observed so far in six open studies of
323 actinic keratoses situated on the face and scalp in Caucasian
populations. Clearance rates already ranged from 71 to 100% after a
single treatment [20, 44]. For illumination purposes, both red (635
nm) or blue lights (417 nm) have been used [18, 44]. Green light
may also be effective, but the user should always bear in mind that
the use of non-red light is not suitable for indications other than
AK, due to the lack of sufficient tissue penetration [13].
In a European, multicenter, randomized prospective study,
MAL-PDT was compared to cryosurgery in the treatment of AK. A total
of 193 patients (95%) with 699 lesions completed the trial.
Patients received either a single treatment with MAL-PDT (repeated
after one week in 8% of cases) or a double freeze-thaw course of
liquid nitrogen cryosurgery. MAL was applied for 3 hours after
slight lesion preparation, followed by illumination with broad
spectrum red light (75 J cm–2). A follow-up visit was
performed 3 months post treatment. The efficacy for MAL-PDT (single
application) was 69% vs. 75% for cryosurgery, which was of no
statistical significance. Thin lesions on the scalp had the highest
response rates (80% and 82% for PDT and cryosurgery, respectively).
Cosmetic outcome, as judged by the investigator, was superior for
MAL-PDT (96% vs. 81%) [37].
In chronology, a comparable trial was conducted in Australia. In
this study MAL-PDT was used as a dual cycle, with two treatment
sessions, one week apart. PDT was compared to a single course of
cryosurgery or placebo in 204 patients. Lesion response was also
assessed after 3 months. A significantly higher complete remission
rate with MAL-PDT was observed (91%) vs. 68% with cryosurgery and
30% with placebo. The cosmetic result was rated excellent in 81% of
MAL-PDT patients vs. 51% treated with cryosurgery [45].
A multicenter, randomized, double-blind, placebo-controlled
study with two MAL-PDT cycles was performed in 80 patients with AK
in the USA. PDT treatment parameters were similar to the above
mentioned trials. Assessment after 3 months revealed a complete
lesion response rate of 89% for MAL-PDT vs. 38% for placebo. An
excellent or good cosmetic outcome was reported in more than 90% of
MAL-treated patients [46].
Dragieva et al. focused in their recent prospective, randomized,
double-blind, placebo-controlled study on MAL-PDT in the treatment
of AK (n = 129) in 17 transplant recipients. As transplant
recipients have an increased propensity to develop multiple AK,
which demonstrate an increased transformation rate into invasive
squamous cell carcinoma, an effective treatment is imperative.
Sixteen weeks following illumination with red light (incoherent
light source, 75 J cm–2, 80 mW cm–2) they
observed complete remission in 13 out of 17 patients. They
concluded that MAL-PDT is a safe and effective treatment for AK in
transplant recipients that may reduce the risk of transformation of
AK to squamous cell carcinoma [9].
Also, for ALA-PDT in the treatment of AK a randomized,
placebo-controlled, uneven-parallel-group study was published
recently. In 243 patients, clinical response, based on lesion
clearing, was assessed at week 8 and 12. Patients were randomized
to receive either vehicle or ALA (Levulan® Kerastick,
DUSA, Wilmington, USA), followed within 14-18 h by
illumination with visible blue light (BLU-U®, DUSA, low
pressure fluorescent lamps). Complete response rates for ALA-PDT
patients with ≥ 75% of the treated lesions clearing at weeks 8 and
12 were 77% and 89%, respectively. In the placebo group, clearing
rates were 18% and 13%. The 12 week clearing rates included 30% of
patients who received a second ALA-PDT course. Moderate to severe
discomfort during illumination was reported by at least 90% of
patients; however, only 3% of patients required discontinuation of
therapy [18].
For the purpose of lowering the amount of side effects of
ALA-PDT, shorter incubation periods (1, 2, 3 h), in
conjunction with pre-treatment with 40% urea in order to enhance
ALA penetration and the use of topical 3% lidocaine hydrochloride
to decrease discomfort were also evaluated. One and 5 months after
therapy in 18 patients with at least 4 non-hypertrophic AK a
reduction of lesions up to 90% in the target area was observed. No
difference was seen between the three incubation periods nor did
pre-treatment with urea or lidocaine have an influence on the
therapeutical outcome [39].
Bowen’s disease & Initial squamous cell carcinoma
Topical PDT using 20% ALA has been extensively assessed in Bowen’s
disease with more than 14 open and three randomized comparison
studies [9, 19, 20, 47]. Cure rates reported so far are the best
for all epithelial cancers or precursors (up to 100%). In a recent
study by Salim et al., ALA-PDT was compared to topical
5-fluorouracil (5-FU). In this bi-center, randomized, phase III
trial, 40 patients with one to three lesions of previously
untreated, histologically proven Bowen’s disease received either
PDT or 5-FU. ALA 20% in an o/w-emulsion was applied 4 h prior
to illumination with an incoherent light source (Paterson lamp,
Photo therapeutics, UK; λem = 630 ± 15 nm; 50-90 mW
cm–2, 100 J cm–2). Treatment with 5-FU was
once daily in week one and then twice daily during weeks 2-4. At
first follow up at week 6, both ALA-PDT and 5-FU application were
repeated, if required. Twenty-nine of 33 lesions (88%) treated with
PDT showed complete response, vs. 67% after 5-FU (22 of 33). After
one year of follow-up, further recurrences reduced the complete
clinical clearance rates to 82% and 42%, respectively [48].
Basal cell carcinoma
Various studies concerning ALA/MAL-PDT for BCC have been performed
in the past years [6, 13, 22, 23, 47, 49-51]. The weighted average
complete clearance rates, after follow-up periods varying between 3
and 36 months, were 87% in 12 studies treating 826 superficial BCCs
and 53% in 208 nodular BCCs [6, 20]. Available compiled data from
other trials have shown an average of 87% for superficial BCCs, and
71% for nodular BCCs [5].
In order to ameliorate poor outcome after PDT of thicker BCC
lesions, Thissen et al. [23] treated 23 patients with 24 nodular
BCCs once with ALA-PDT (incoherent red light; 100 mW
cm–2, 120 J cm–2) three weeks after debulking
of the BCCs. The former tumor areas were excised three months later
and histopathologically evaluated for residual tumor. Twenty-two
(92%) of the 24 nodular BCCs showed both clinically and
histologically a complete response.
In a prospective phase III trial comparing ALA-PDT with
cryosurgery, Wang et al. [51] included 88 superficial and nodular
BCCs. Recruited individuals were only allowed to have one lesion
included in the trial. A 20% ALA/water-in-oil cream was applied for
6 h under an occlusive dressing, followed by irradiation with
a laser at 635 nm (80 mW cm–2, 60 J cm–2). In
the cryosurgery arm, lesions were treated with liquid nitrogen in
the open spray technique using two freeze-thaw cycles for
25-30 s each time. After 3 months, punch biopsies were
performed and revealed a recurrence rate of 25% in the PDT group
and 15% in the cryosurgery group. However, the clinical recurrence
rates were only 5% for ALA-PDT and 13% for cryosurgery. The
discrepancy between the clinical appearance of the treated lesion
and the actual status in histology is problematic, as tumor
recurrence can be masked. In the PDT treated group a better
cosmetic outcome and a shorter healing time was documented.
Solèr and colleagues [22] studied the long term effects of
MAL-PDT in 59 patients with 350 BCCs. Nodular tumors were curetted
before PDT and MAL (160 mg/g) was applied to all to all tumors for
24 h or 3 h prior to irradiation with a broad-band
halogen light source (50-200 J cm–2). Patients were
followed for 2-4 years (mean 35 months). Overall cure rate was 79%,
cosmetic outcome was excellent or good in 98% of the completely
responding lesions.
In a recent open, uncontrolled, prospective, multicenter trial,
patients with both superficial and/or nodular BCC who were at risk
of complications, poor cosmetic outcome, disfigurement and/or
recurrence using conventional therapy were studied. Ninety-four
patients were treated with a single cycle of MAL-PDT involving two
treatment sessions one week apart, and followed up at three months,
at which time non-responders were retreated. The clinical lesion
remission rate after three months was 92% for superficial BCC, 87%
for nodular BCC. The histological cure rate at this time point was
85% in superficial BCC and 75% in nodular BCC. At 24 months after
treatment, the overall lesion recurrence rate was 18% [49].
In another European multicenter, open, randomized trial, MAL-PDT
for nodular BCC was compared with surgery. A total of 101 patients
were included and received either PDT twice, 7 days apart (75 J
cm–2 red light) or surgical excision. The primary end
point of this trial was the clinically assessed lesion clearance at
3 months after treatment, besides cosmesis. The 3 month cure rate
was similar with MAL-PDT or surgery (91% vs. 98%), the 24 month
recurrence rate was 10% with MAL and 2% with surgery. The cosmetic
result was rated good/excellent in 85% of the patients receiving
PDT vs. 33% with surgery [50].
In a comparative trial in Australia, MAL-PDT for nodular BCC was
compared to placebo. Lesions from 66 patients were treated either
with two sessions of either placebo or MAL-PDT in a randomized,
double-blind controlled study. If there was no complete response 3
months after initial treatment, lesions were excised. After six
months, complete remission rate was 73% for MAL-PDT compared to 21%
of placebo [38].
ALA-PDT can be used also for adjuvant therapy in combination
with Mohs micrographic surgery, as reported recently by Kuijpers et
al. [52]. In four patients, who underwent Mohs micrographic surgery
for extensive BCC, first the central infiltrating tumor part was
excised. After re-epithelialization, ALA-PDT of the surrounding
tumor rims (2-5 cm) bearing remaining superficial tumor parts,
was performed. This led to a complete remission of the tumors with
excellent clinical and cosmetic results (follow-up period up to 27
months) [52].
However, even if all clinical studies qualify PDT as an
effective treatment of BCC, Mohs micrographic surgery shows
generally higher cure rates as compared to PDT. Besides, the
relatively short follow up of most of the studies performed has to
be considered. Mandatory indications for surgical treatment are
different histological subtypes like pigmented or morpheic BCCs or
BCCs located in the area of the facial embryonic fusion clefts as
well as all BCCs thicker than 3 mm if no debulking procedure
is performed prior to PDT.
Therapeutic applications – non-oncologic indications
In contrast to PDT of tumors, where cellular destruction is the
main goal of the therapy, in PDT of inflammatory skin conditions
the modulation of cellular functions is probably the main role. The
therapeutic protocols differ significantly from those used for the
treatment of tumors. Significantly lower doses of both light and
photosensitizer are used in the context of a “low-dose-PDT” for the
treatment of inflammatory skin conditions. However, multiple
treatments are necessary to achieve the desired therapeutic effects
with little or no side effects. So far, the best results for PDT in
inflammatory skin conditions have been achieved with
5-aminolevulinic acid (ALA). However, for non-oncologic skin
disease, there is a lack of controlled clinical trials so far, but
there are numerous publications reporting a remarkable
therapeutical benefit following PDT of e.g. acne vulgaris,
localized scleroderma, psoriasis or genital warts, with no severe
side effects [53-56]. Therefore, it is very likely that PDT will
also be of great value for a choice of non-oncologic indications.
Psoriasis vulgaris
The data provided in the literature for the treatment of psoriasis
vulgaris is very controversial. It has been shown that ALA is
capable of penetrating the parakeratotic stratum corneum in the
area of a psoriatic plaque and selectively accumulating in the
diseased tissue [57, 58]. Boehncke et al. [59] compared the
efficacy of ALA-PDT in three patients with a conventional topical
treatment using dithranol in a half-side trial. The lesions were
incubated with a 10% ALA-ointment for 5 hours followed by an
irradiation with an incoherent light source (600-700 nm, 70 mW
cm–2, 25 J cm–2). This treatment was
performed once weekly for three weeks, the plaques on the other
side received anthraline on a daily base. The time to reach
complete remission of psoriatic plaques was similar in both
treatment settings. In a recent study performed by Collins and
co-workers, 22 patients with psoriasis were treated with ALA-PDT
[60]. After application of a 20% ALA-preparation for 4 hours the
plaques were illuminated using an incoherent light projector
(400-650 nm, 300 mW cm–2, 2-16 J cm–2). In 7
of the 22 patients some of the treated plaques healed. In a further
study the same working group studied the effect of multiple
treatments with ALA-PDT [61]. Ten patients with chronic
plaque-stage psoriasis have been treated up to 3 times a week for a
maximum of 12 treatments. A 20% ALA-emulsion was applied for 4
hours, afterwards the plaques were irradiated with a broadband
light source at 15 mW cm–2 and 8 J cm–2. In
eight patients a clinical success was achieved. However, all
patients complained of pain during the irradiation process. Beatti
et al. [62] reported a lack of efficacy and tolerability of topical
PDT for psoriasis in comparison with narrowband UVB phototherapy.
Furthermore, Radakovic-Fijan et al. [63] performed a randomized,
intra-patient comparison study on topical ALA-PDT in psoriatic
patients and documented not only an unsatisfactory clinical
response but also frequent occurrence of pain during and after
irradiation. They concluded topical ALA-PDT to be an inadequate
treatment option for psoriasis.
The pain seems to be dose-dependent for both the photosensitizer
and the light and it fades within a period of two days after
therapy. It is therefore important to study whether both light dose
and drug concentration can be lowered following the concept of a
“low-dose-PDT” with the goal of reduction of pain without hampering
with the efficacy of the therapy.
Another side effect reported in the literature is Koebnerization
[64]. One patient receiving PDT with ALA for the treatment of
actinic keratosis and initial squamous cell carcinoma developed
psoriatic lesions on her lower leg two days after PDT.
The impact of PDT on psoriasic lesions is yet not fully clear
since the therapeutic protocols used differ significantly and so
far no controlled clinical trials with high numbers of patients are
available. However, potential advantages do exist for PDT in
contrast to the UV-irradiation, as there is no evidence of an
increased risk of cutaneous cancer developing after PDT. Some
investigations also show that the number of treatments needed for
therapeutic success seems to be lower, in comparison to
PUVA-therapy.
HPV-induced skin diseases
Vulgar warts on hands and feet, plain warts or genital warts
(condylomata acuminata) are common skin diseases induced by human
papilloma viruses (HPV) [65]. Even after surgical removal or
application of cytotoxic drugs a high rate of recurrences can be
observed. Since the fast proliferating cells in viral acanthomas
accumulate ALA-induced PpIX selectively [66, 67] and since ALA-PDT
has virucidal properties [68] PDT is introduced as a possible
alternative treatment modality.
Vulgar warts
Kennedy et al. did not achieve success in the treatment of vulgar
warts with ALA-PDT in their study published 1990 [12].
Correspondingly, Amman et al. did not report successful topical
ALA-PDT in the treatment of recalcitrant vulgar warts [69]. Only in
one out of six patients was a complete remission achieved within
two months after PDT [69]. The reason for the treatment failures
was probably the less effective cutaneous penetration of ALA due to
the prominent hyperkeratosis in vulgar warts. Smetana et al. tried
to increase the effectiveness of ALA-PDT by adding the penetration
enhancers EDTA (2%) and DMSO (2%). With this formulation they were
able to treat successfully widespread vulgar warts in a patient who
received a kidney transplant. Within a follow-up period of two
years no recurrence was observed [68].
Stender et al. conducted a comparative trial in 30 patients with
recalcitrant warts. After incubation with a 20% ALA-cream for five
hours irradiation was performed using a slide protector with
different wavelengths and a total light dose of 40 J
cm–2. Previous to ALA-PDT, keratolysis of the warts was
performed [70]. Following PDT with white light, which was performed
three times, complete remission was significantly higher (CR 73%)
than after PDT performed three times with blue light (CR 28%) or
red light (CR 42%) or with the use of cryotherapy as a comparative
treatment modality (CR 20%). Within the follow-up period of 12
months no further recurrences were observed. This study was then
followed by a double-blinded, randomized trial by the same working
group in 45 patients, which consolidated the results of the first
pilot-trial [55]. Also in this trial it could be shown that ALA-PDT
is successful in the treatment of recalcitrant warts of the hand
and the soles of the feet. Irradiation was performed with an
incoherent light source (Waldmann PDT 1200L, 590-700 nm) at a light
intensity of 50 mW cm–2 and a total light source of 70 J
cm–2. The procedure was repeated after one and after two
weeks. If the warts were still present after 7 weeks, a therapeutic
cycle (3 treatments in weekly increments) was again performed. The
patients were advised to debride their warts prior to PDT. The
trial resulted in a complete remission of warts in 56% of cases in
the ALA-PDT treated group in comparison to 42% in the placebo
group. A major side-effect of this treatment is pain [55].
Fabbrocini et al. [71] performed another placebo-controlled
trial where 64 plantar warts were treated with 20% ALA after
keratolysis. 57 warts served as controls (treated only with the
emollient without drug). Irradiation was performed with an
incoherent light source (400-700 nm, 50 J cm–2), it was
repeated depending on the results up to 3 times per week within a
period of 3 weeks. Two months after therapy 75% of the warts
treated with ALA-PDT showed complete remission, whereas only 22.8%
of the warts treated with placebo showed complete remission.
These results show that ALA-PDT in combination with a sufficient
keratolysis is a successful alternative in the treatment of
recalcitrant warts. Again, the main drawback is pain during
irradiation which probably will hinder a broad use of PDT,
especially in children.
Genital warts
Most of the destructive therapeutic modalities of anogenital
condylomata like electrodesiccation or vaporisation using a
CO2-laser only lead to a destruction of the visible part
of the warts, whereas subclinical lesions will not be treated
effectively and cause the high rate of recurrence. ALA-PDT could be
of great interest for this indication especially due to the
selective destruction of subclinical virus-shedding areas, helping
to reduce the high rate of recurrence.
Since a selective enrichment of PpIX in warts is the main
prerequisite for the therapeutic efficacy, Fehr et al. [66] studied
the fluorescence of PpIX after topical application of ALA in vulvar
condylomata in 22 patients. Three to six hours after application of
ALA a homogeneous distribution of PpIX was seen in the epidermis.
After 24 hours fluorescence was only seen in the region of the
granular layer. Similar results were reported by Ross et al. [67].
They were able to show a selective accumulation of PpXI in
condyloma after topical application of ALA. Two hours following
start of incubation, a higher selectivity compared to the
surrounding normal skin was already achieved. In a pilot study, 7
patients with anogenital warts were treated with a cream containing
20% ALA in combination with lidocaine hydrochloride. The incubation
time was 14 hours. After this time period a local anaesthetic was
again applied for an additional two hours. Afterwards the area was
irradiated with an argon ion-pumped dye laser (630 nm, 75-150 mW
cm–2, 100 J cm–2). Four out of seven patients
treated with ALA-PDT showed a complete remission [72]. The most
important goal in the treatment of anogenital warts is the
reduction of the high rate of recurrences after conventional
treatment modalities. Perhaps the combination of classic ablative
treatments with PDT, which contributes to a selective destruction
of subclinical virus-shedding areas, might be of help.
Acne vulgaris
PDT in the treatment of acne is based on the fact that Propioni
bacterium acnes contains endogenous porphyrins, in particular
coproporphyrin III [56]. Therefore, visible as well as blue light
phototherapy is effective. Hongcharu et al. [73] treated 22
patients with acne vulgaris on the back in an open, prospective
trial with ALA-PDT. Eleven patients received a single treatment,
the other 11 patients were treated 4 times. ALA (20%) was applied
occlusively for 3 hours, afterwards the area was irradiated with
red light (550-700 nm, 150 J cm–2). The phototoxic
reaction after ALA-PDT was restricted selectively to areas
containing sebaceous glands. The function of the sebaceous glands
was altered and also the numbers of bacteria in the follicles was
reduced. Histopathology showed acute cytotoxic damage of the
sebaceous glands. Clinically a significant improvement of the
inflammatory acne lesions was observed after ALA-PDT which was
sustained after multiple PDT-sessions for more than 20 weeks.
Although ALA-PDT was very effective in the treatment of acne,
severe side effects were observed: pain, erythema, edema, transient
hyperpigmentation, sometimes even blistering, purpura or an acute
acneiform rash. These results were in accordance with Itoh et al.
[54]. Twenty-three patients with acne vulgaris resistant to
standard therapy in the face were treated with ALA-PDT. An emulsion
containing 20% ALA was applied for 4 hours and irradiated with
polychromatic light from a halogen lamp (600-700 nm, 17 mW
cm–2, 13 J cm–2). In all patients acne
improved and the development of new acne spots was reduced up to 6
months following PDT. Considerable side effects were pain, edema,
crust formation, erythema and hyperpigmentation [54]. Pollock et
al. [74] showed a statistically significant reduction in
inflammatory acne lesions after three courses of ALA-PDT performed
within three weeks. However, as they documented no statistically
significant reduction in P. acnes, they suggested an alternative
mode of action for ALA-PDT in acne.
These investigations indicate that ALA-PDT is very potent in the
treatment of acne vulgaris. However, with the present protocols the
massive side effects do not justify routine use. Perhaps
significantly lower doses of both light and photosensitizer
combined with a higher number of treatments might improve the
efficacy and lower the rate of side effects.
Morphea and lichen sclerosus
Morphea is a chronic inflammatory reaction of the skin which
results after an inflammatory phase in a circumscribed sclerosis of
the skin. Although the prognosis of morphea is mostly favourable,
widespread lesions can lead to contractions of joints and
immobilisation. Although PUVA or bath-PUVA therapy as well as high
dose UVA1 are effective in the treatment of morphea, the
limited penetration depth of UV-light as well as the long term side
effects of UV-therapy (carcinogenic potential, skin aging) should
be considered. In a clinical observation, 10 patients with morphea,
who did not respond to bath-PUVA, penicillin-infusions and local
therapies were treated with topical ALA-PDT. After application of
ALA-gel (3%) for 6 hours, irradiation was performed with an
incoherent light source (PDT 1200 L, 40 mW cm–2, 10
J cm–2). This treatment was repeated once or twice
weekly for 3 to 6 months [53]. The mean number of therapies was 26
± 8. Morphea was judged before, during and after therapy using a
durometer [75] or a clinical score [76]. In every patient both
scores were reduced significantly at the end of therapy. Slight
burning sensation or mild pruritus as well as transient
hyperpigmentation in the treated area were reported as side effects
during the irradiation sessions. Even after two years no further
progression and recurrence was observed. However, in some patients
new morphea lesions developed at sides previously not treated with
PDT.
The effectivity of ALA-PDT was also reported for lichen
sclerosus [77]. Twelve women with lichen sclerosus and severe
pruritus were treated with a 20% ALA-formulation followed by
irradiation with light from an argon ion-pumped dye laser (635 nm,
70 mW cm–2, 80 J cm–2). If the pruritus did
not resolve after the first treatment, the patients were retreated
within 1-3 weeks after the first therapy. PDT was tolerated well,
even 6-8 weeks after the last session pruritus had improved in 10
out of 12 patients.
Beside these indications, in small case series, encouraging
results after ALA-PDT were obtained in actinic cheilitis [78],
Nevus sebaceous [79] and Epidermodysplasia verruciformis [80].
Conclusion
PDT in dermatology is approved for the treatment of superficial
basal cell carcinoma, actinic keratoses and also Bowen’s disease,
in many countries all over the world. Numerous publications have
demonstrated the effectiveness of PDT and also for the treatment of
other cutaneous malignancies and non-oncologic indications [10].
However, controlled clinical trials are required to clarify whether
PDT of non-oncologic indications can demonstrate superiority over
existing, approved therapeutic modalities. The proven advantages of
PDT include the simultaneous treatment of multiple tumors and
incipient lesions, relatively short healing times, good patient
tolerance and an excellent cosmesis. Very promising is the
potential tumor control in immunocompromised patients (i.e.
transplant recipients). Cost-effectiveness analysis indicates that
with relatively low costs for permanent equipment, topical PDT is
probably no more expensive than conventional therapy when its lower
side-effect profile is considered [20].
References
1 Raab O. Wirkung fluorescierender. Stoffe auf Infusorien,
1900.
2 Szeimies RM, Dräger J, Abels C, et al.
History of photodynamic therapy in dermatology. In:
Calzavara-Pinton PG, Szeimies RM, Ortel B, eds.
Photodynamic therapy and Fluorescence Diagnosis in Dermatology.
Amsterdam: Elsevier, 2001: 3-16.
3 Dougherty TJ, Grindey GB, Fiel R, et al.
Photoradiation therapy. II. Cure of animal tumors with
hematoporphyrin and light. J Natl Cancer Inst 1975; 55: 115-21.
4 Dougherty TJ, Kaufman JE, Goldfarb A,
et al. Photoradiation therapy for the treatment of malignant
tumors. Cancer Res 1978; 38: 2628-35.
5 Zeitouni NC, Oseroff AR, Shieh S. Photodynamic
therapy for nonmelanoma skin cancers. Current review and update.
Mol Immunol 2003; 39: 1133-6.
6 Marmur ES, Schmults CD, Goldberg DJ. A review
of laser and photodynamic therapy for the treatment of nonmelanoma
skin cancer. Dermatol Surg 2004; 30: 264-71.
7 Braathen LR. Photodynamic therapy. Tidsskr Nor Laegeforen
2001; 121: 2635-6.
8 Dragieva G, Hafner J, Dummer R, et al.
Topical photodynamic therapy in the treatment of actinic keratoses
and Bowen’s disease in transplant recipients. Transplantation 2004;
77: 115-21.
9 Dragieva G, Prinz BM, Hafner J, et al. A
randomized controlled clinical trial of topical photodynamic
therapy with methyl aminolaevulinate in the treatment of actinic
keratoses in transplant recipients. Br J Dermatol 2004; 151:
196-200.
10 Morton CA. Photodynamic therapy for nonmelanoma skin
cancer--and more? Arch Dermatol 2004; 140: 116-20.
11 Schweitzer VG. PHOTOFRIN-mediated photodynamic therapy
for treatment of early stage oral cavity and laryngeal
malignancies. Lasers Surg Med 2001; 29: 305-13.
12 Kennedy JC, Pottier RH, Pross DC. Photodynamic
therapy with endogenous protoporphyrin IX: basic principles and
present clinical experience. J Photochem Photobiol B 1990; 6:
143-8.
13 Szeimies RM, Karrer S, Abels C, et al.
Photodynamic therapy in dermatology. In: Krutmann J,
Hönigsmann H, Elmets CA, Bergstresser PR, eds.
Dermatological phototherapy and photodiagnostic methods. Berlin:
Springer, 2001: 209-47.
14 Baas P, Saarnak AE, Oppelaar H, et al.
Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal
cell carcinoma: a phase I/II study. Br J Dermatol 2001; 145:
75-8.
15 Lui H, Hobbs L, Tope WD, et al.
Photodynamic therapy of multiple nonmelanoma skin cancers with
verteporfin and red light-emitting diodes: two-year results
evaluating tumor response and cosmetic outcomes. Arch Dermatol
2004; 140: 26-32.
16 Szeimies RM, Abels C, Fritsch C, et al.
Wavelength dependency of photodynamic effects after sensitization
with 5-aminolevulinic acid in vitro and in vivo. J Invest Dermatol
1995; 105: 672-7.
17 Brown SB. The role of light in the treatment of
non-melanoma skin cancer using methyl aminolevulinate. J Dermatolog
Treat 2003; 14(Suppl 3): 11-4.
18 Piacquadio DJ, Chen DM, Farber HF, et al.
Photodynamic therapy with aminolevulinic acid topical solution and
visible blue light in the treatment of multiple actinic keratoses
of the face and scalp: investigator-blinded, phase 3, multicenter
trials. Arch Dermatol 2004; 140: 41-6.
19 Morton CA, Whitehurst C, Moore JV, et al.
Comparison of red and green light in the treatment of Bowen’s
disease by photodynamic therapy. Br J Dermatol 2000; 143:
767-72.
20 Morton CA, Brown SB, Collins S, et al.
Guidelines for topical photodynamic therapy: report of a workshop
of the British Photodermatology Group. Br J Dermatol 2002; 146:
552-67.
21 Haller JC, Cairnduff F, Slack G, et al.
Routine double treatments of superficial basal cell carcinomas
using aminolaevulinic acid-based photodynamic therapy. Br J
Dermatol 2000; 143: 1270-5.
22 Soler AM, Warloe T, Berner A, et al. A
follow-up study of recurrence and cosmesis in completely responding
superficial and nodular basal cell carcinomas treated with methyl
5-aminolaevulinate-based photodynamic therapy alone and with prior
curettage. Br J Dermatol 2001; 145: 467-71.
23 Thissen MR, Schroeter CA, Neumann HA.
Photodynamic therapy with delta-aminolaevulinic acid for nodular
basal cell carcinomas using a prior debulking technique. Br J
Dermatol 2000; 142: 338-9.
24 Juzeniene A, Juzenas P, Ma LW, et al.
Effectiveness of different light sources for 5-aminolevulinic acid
photodynamic therapy. Lasers Med Sci 2004; 19: 139-49.
25 Brancaleon L, Moseley H. Laser and non-laser light
sources for photodynamic therapy. Lasers Med Sci 2002; 17:
173-86.
26 Karrer S, Baumler W, Abels C, et al.
Long-pulse dye laser for photodynamic therapy: investigations in
vitro and in vivo. Lasers Surg Med 1999; 25: 51-9.
27 Szeimies RM, Hein R, Baumler W, et al. A
possible new incoherent lamp for photodynamic treatment of
superficial skin lesions. Acta Derm Venereol 1994; 74: 117-9.
28 Alexiades-Armenakas MR, Geronemus RG.
Laser-mediated photodynamic therapy of actinic keratoses. Arch
Dermatol 2003; 139: 1313-20.
29 Soler AM, Angell-Petersen E, Warloe T,
et al. Photodynamic therapy of superficial basal cell
carcinoma with 5-aminolevulinic acid with dimethylsulfoxide and
ethylendiaminetetraacetic acid: a comparison of two light sources.
Photochem Photobiol 2000; 71: 724-9.
30 Clark C, Bryden A, Dawe R, et al. Topical
5-aminolaevulinic acid photodynamic therapy for cutaneous lesions:
outcome and comparison of light sources. Photodermatol Photoimmunol
Photomed 2003; 19: 134-41.
31 Varma S, Wilson H, Kurwa HA, et al.
Bowen’s disease, solar keratoses and superficial basal cell
carcinomas treated by photodynamic therapy using a large-field
incoherent light source. Br J Dermatol 2001; 144: 567-74.
32 Yang CH, Lee JC, Chen CH, et al.
Photodynamic therapy for bowenoid papulosis using a novel
incoherent light-emitting diode device. Br J Dermatol 2003; 149:
1297-9.
33 Morton CA. Methyl aminolevulinate (Metvix) photodynamic
therapy – practical pearls. J Dermatolog Treat 2003; 14(Suppl 3):
23-6.
34 Bissonnette R, Bergeron A, Liu Y. Large
surface photodynamic therapy with aminolevulinic acid: treatment of
actinic keratoses and beyond. J Drugs Dermatol 2004; 3:
S26-S31.
35 Stender IM, Bech-Thomsen N, Poulsen T,
et al. Photodynamic therapy with topical delta-aminolevulinic
acid delays UV photocarcinogenesis in hairless mice. Photochem
Photobiol 1997; 66: 493-6.
36 Moore JV, Allan E. Pulsed ultrasound measurements
of depth and regression of basal cell carcinomas after photodynamic
therapy: relationship to probability of 1-year local control. Br J
Dermatol 2003; 149: 1035-40.
37 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:
258-62.
38 Foley P. Clinical efficacy of methyl aminolevulinate
(Metvix) photodynamic therapy. J Dermatolog Treat 2003; 14(Suppl
3): 15-22.
39 Touma D, Yaar M, Whitehead S, et al. A
trial of short incubation, broad-area photodynamic therapy for
facial actinic keratoses and diffuse photodamage. Arch Dermatol
2004; 140: 33-40.
40 Pagliaro J, Elliott T, Bulsara M, King C,
Vinciullo C. Cold air analgesia in photodynamic therapy of
basal cell carcinomas and Bowen’s disease: an effective addition to
treatment: a pilot study. Dermatol Surg 2004; 30: 63-6.
41 Wulf HC, Philipsen P. Allergic contact dermatitis
to 5-aminolaevulinic acid methylester but not to 5-aminolaevulinic
acid after photodynamic therapy. Br J Dermatol 2004; 150:
143-5.
42 Guillen C, Sanmartin O, Escudero A,
et al. Photodynamic therapy for in situ squamous cell
carcinoma on chronic radiation dermatitis after photosensitization
with 5-aminolaevulinic acid. J Eur Acad Dermatol Venereol 2000; 14:
298-300.
43 Babilas P, Landthaler M, Szeimies RM. Actinic
keratoses. Hautarzt 2003; 54(6): 551-60.
44 Sidoroff A. Actinic keratosis. In:
Calzavara-Pinton PG, Szeimies RM, Ortel B, eds.
Photodynamic therapy and Fluorescence Diagnosis in Dermatology.
Amsterdam: Elsevier, 2001: 199-216.
45 Freeman M, Vinciullo C, Francis D, et al.
A comparison of photodynamic therapy using topical methyl
aminolevulinate (Metvix) with single cycle cryotherapy in patients
with actinic keratosis: a prospective, randomized study. J
Dermatolog Treat 2003; 14: 99-106.
46 Pariser DM, Lowe NJ, Stewart DM, et al.
Photodynamic therapy with topical methyl aminolevulinate for
actinic keratosis: results of a prospective randomized multicenter
trial. J Am Acad Dermatol 2003; 48: 227-32.
47 Morton CA, Whitehurst C, McColl JH,
et al. Photodynamic therapy for large or multiple patches of
Bowen disease and basal cell carcinoma. Arch Dermatol 2001; 137:
319-24.
48 Salim A, Leman JA, McColl JH, et al.
Randomized comparison of photodynamic therapy with topical
5-fluorouracil in Bowen’s disease. Br J Dermatol 2003; 148:
539-43.
49 Horn M, Wolf P, Wulf HC, et al. Topical
methyl aminolaevulinate photodynamic therapy in patients with basal
cell carcinoma prone to complications and poor cosmetic outcome
with conventional treatment. Br J Dermatol 2003; 149: 1242-9.
50 Rhodes LE, de Rie M, Enstrom Y, et al.
Photodynamic therapy using topical methyl aminolevulinate vs
surgery for nodular basal cell carcinoma: results of a multicenter
randomized prospective trial. Arch Dermatol 2004; 140: 17-23.
51 Wang I, Bendsoe N, Klinteberg CA, et al.
Photodynamic therapy vs. cryosurgery of basal cell carcinomas:
results of a phase III clinical trial. Br J Dermatol 2001; 144:
832-40.
52 Kuijpers DI, Smeets NW, Krekels GA,
et al. Photodynamic therapy as adjuvant treatment of extensive
basal cell carcinoma treated with Mohs micrographic surgery.
Dermatol Surg 2004; 30: 794-8.
53 Karrer S, Abels C, Landthaler M, et al.
Topical photodynamic therapy for localized scleroderma. Acta Derm
Venereol 2000; 80: 26-7.
54 Itoh Y, Ninomiya Y, Tajima S, et al.
Photodynamic therapy of acne vulgaris with topical
delta-aminolaevulinic acid and incoherent light in Japanese
patients. Br J Dermatol 2001; 144: 575-9.
55 Stender IM, Na R, Fogh H, et al.
Photodynamic therapy with 5-aminolaevulinic acid or placebo for
recalcitrant foot and hand warts: randomised double-blind trial.
Lancet 2000; 355: 963-6.
56 Ibbotson SH. Topical 5-aminolaevulinic acid photodynamic
therapy for the treatment of skin conditions other than
non-melanoma skin cancer. Br J Dermatol 2002; 146: 178-88.
57 Bissonnette R, Zeng H, McLean DI, et al.
Oral aminolevulinic acid induces protoporphyrin IX fluorescence in
psoriatic plaques and peripheral blood cells. Photochem Photobiol
2001; 74: 339-45.
58 Stringer MR, Collins P, Robinson DJ,
et al. The accumulation of protoporphyrin IX in plaque
psoriasis after topical application of 5-aminolevulinic acid
indicates a potential for superficial photodynamic therapy. J
Invest Dermatol 1996; 107: 76-81.
59 Boehncke WH, Sterry W, Kaufmann R. Treatment
of psoriasis by topical photodynamic therapy with polychromatic
light. Lancet 1994; 343: 801.
60 Collins P, Robinson DJ, Stringer MR,
et al. The variable response of plaque psoriasis after a
single treatment with topical 5-aminolaevulinic acid photodynamic
therapy. Br J Dermatol 1997; 137: 743-9.
61 Robinson DJ, Collins P, Stringer MR,
et al. Improved response of plaque psoriasis after multiple
treatments with topical 5-aminolaevulinic acid photodynamic
therapy. Acta Derm Venereol 1999; 79: 451-5.
62 Beattie PE, Dawe RS, Ferguson J, et al.
Lack of efficacy and tolerability of topical PDT for psoriasis in
comparison with narrowband UVB phototherapy. Clin Exp Dermatol
2004; 29: 560-2.
63 Radakovic-Fijan S, Blecha-Thalhammer U,
Schleyer V, et al. Topical aminolaevulinic acid-based
photodynamic therapy as a treatment option for psoriasis? Results
of a randomized, observer-blinded study. Br J Dermatol 2005; 152:
279-83.
64 Stender IM, Wulf HC. Kobner reaction induced by
photodynamic therapy using delta-aminolevulinic acid. A case
report. Acta Derm Venereol 1996; 76: 392-3.
65 Brentjens MH, Yeung-Yue KA, Lee PC,
et al. Human papillomavirus: a review. Dermatol Clin 2002; 20:
315-31.
66 Fehr MK, Chapman CF, Krasieva T, et al.
Selective photosensitizer distribution in vulvar condyloma
acuminatum after topical application of 5-aminolevulinic acid. Am J
Obstet Gynecol 1996; 174: 951-7.
67 Ross EV, Romero R, Kollias N, et al.
Selectivity of protoporphyrin IX fluorescence for condylomata after
topical application of 5-aminolaevulinic acid: implications for
photodynamic treatment. Br J Dermatol 1997; 137: 736-42.
68 Smetana Z, Malik Z, Orenstein A, et al.
Treatment of viral infections with 5-aminolevulinic acid and light.
Lasers Surg Med 1997; 21: 351-8.
69 Ammann R, Hunziker T, Braathen LR. Topical
photodynamic therapy in verrucae. A pilot study. Dermatology 1995;
191: 346-7.
70 Stender IM, Lock-Andersen J, Wulf HC.
Recalcitrant hand and foot warts successfully treated with
photodynamic therapy with topical 5-aminolaevulinic acid: a pilot
study. Clin Exp Dermatol 1999; 24: 154-9.
71 Fabbrocini G, Di Costanzo MP, Riccardo AM,
et al. Photodynamic therapy with topical delta-aminolaevulinic
acid for the treatment of plantar warts. J Photochem Photobiol B
2001; 61: 30-4.
72 Frank RG, Bos JD. Photodynamic therapy for
condylomata acuminata with local application of 5-aminolevulinic
acid. Genitourin Med 1996; 72: 70-1.
73 Hongcharu W, Taylor CR, Chang Y, et al.
Topical ALA-photodynamic therapy for the treatment of acne
vulgaris. J Invest Dermatol 2000; 115: 183-92.
74 Pollock B, Turner D, Stringer MR, et al.
Topical aminolaevulinic acid-photodynamic therapy for the treatment
of acne vulgaris: a study of clinical efficacy and mechanism of
action. Br J Dermatol 2004; 151: 616-22.
75 Seyger MM, van den Hoogen FH, de Boo T,
et al. Reliability of two methods to assess morphea: skin
scoring and the use of a durometer. J Am Acad Dermatol 1997; 37:
793-6.
76 Rook AH, Freundlich B, Jegasothy BV,
et al. Treatment of systemic sclerosis with extracorporeal
photochemotherapy. Results of a multicenter trial. Arch Dermatol
1992; 128: 337-46.
77 Hillemanns P, Untch M, Prove F, et al.
Photodynamic therapy of vulvar lichen sclerosus with
5-aminolevulinic acid. Obstet Gynecol 1999; 93: 71-4.
78 Stender IM, Wulf HC. Photodynamic therapy with
5-aminolevulinic acid in the treatment of actinic cheilitis. Br J
Dermatol 1996; 135: 454-6.
79 Dierickx CC, Goldenhersh M, Dwyer P,
et al. Photodynamic therapy for nevus sebaceus with topical
delta-aminolevulinic acid. Arch Dermatol 1999; 135: 637-40.
80 Karrer S, Szeimies RM, Abels C, et al.
Epidermodysplasia verruciformis treated using topical
5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 1999;
140: 935-8.
|
Printable version
Version PDF
