Acta Derm Venereol 2005; 85: 483–490

REVIEW ARTICLE

Photodynamic Therapy for Non-melanoma Skin Cancer

Rolf-Markus SZEIMIES1, Colin A. MORTON2, Alexis SIDOROFF3 and Lasse R. BRAATHEN4
1
Klinik und Poliklinik für Dermatologie, Klinikum der Universität Regensburg, Regensburg, Germany, 2Department of Dermatology, Falkirk Royal
Infirmary, Falkirk, UK, 3Universitätsklinik für Dermatologie und Venerologie, Medizinische Universität Innsbruck, Innsbruck, Austria, and
4
Dermatologische Universitätsklinik und Poliklinik Inselspital, Bern, Switzerland

Photodynamic therapy is a treatment modality that has 5-aminolevulinic acid (ALA) or methyl aminolevulinate
been shown to be effective mainly for the dermato- (MAL) are of practical concern. The main drawback for
oncologic conditions: actinic keratosis, Bowen’s disease, systemic photosensitizing drugs is their prolonged
in situ squamous cell carcinoma and basal cell carci- generalized phototoxicity (3). Therefore topical photo-
noma. Recent work has focused on the development and sensitizers are preferred for use in dermatology.
evaluation of topical photosensitizers like the haem Meanwhile drugs like MAL have reached approval
precursor 5-aminolevulinic acid or its methyl ester, both status for epithelial cancers or their precursors through-
inducing photosensitizing porphyrins. These drugs do not out the world, ALA in the US, and there is growing
induce strong generalized cutaneous photosensitization, interest in the use of PDT not only for non-melanoma
unlike the systemically applied porphyrins or their skin cancer but also for other skin tumours like
derivatives. For dermatological purposes incoherent lamps lymphoma or for tumour surveillance in transplant
or light-emitting diode arrays can be used for light patients (4–6).
activation. Cure rates reported for very superficial lesions
(tumour thickness v2–3 mm) are comparable to those
achieved by other therapeutic modalities. Photodynamic PHOTOSENSITIZERS
therapy is a minimally invasive therapy associated with The first drugs used for PDT were topically applied dyes
excellent cosmetic results. For actinic keratosis and basal like eosin red or erythrosine. Those photosensitizers
cell carcinoma, methyl aminolevulinate-photodynamic were used exactly 100 years ago by Georges Dreyer in
therapy is already approved in Europe, Australia and Copenhagen and Albert Jesionek in Munich (1903/1904)
New Zealand, and is now also approved for actinic to treat conditions like pityriasis versicolor, psoriasis,
keratosis in the US. Key words: photodynamic therapy; molluscum contagiosum, syphilis, lupus vulgaris or skin
fluorescence detection; aminolevulinic acid; methyl cancer (1). Unfortunately the experiments were aban-
aminolevulinate; skin cancer. doned due to lack of long-term remissions and severe
(Accepted May 24, 2005.) side effects. Since 1968 the tumour localizing effects of
porphyrins were studied. This resulted in a renaissance
Acta Derm Venereol 2005; 85: 483–490. of PDT in the late 1970s by Thomas Dougherty who
Prof. Dr. med. Rolf-Markus Szeimies, Klinik und Poliklinik used haematoporphyrin derivative (HPD) and later its
für Dermatologie, Klinikum der Universität Regensburg, purified derivative porfimer sodium for the treatment of
D-93042 Regensburg, Germany, E-mail: Rolf-Markus. primary cancer of the skin or cutaneous metastases (1,
[email protected] 2). The main problem in the use of HPD or porfimer
sodium is the prolonged skin photosensitization, which
At the beginning of the 20th century Hermann von lasts for several weeks (7). A desired topical application
Tappeiner, then director of the Institute of is also not possible since the rather big molecules
Pharmacology of the University of Munich, first coined (tetrapyrrol rings) do not penetrate the skin. Therefore
the term ‘photodynamic reaction’ (1). Already at that the introduction of porphyrin precursors like ALA by
time it was known that photodynamic therapy (PDT) Kennedy and co-workers in 1990, and later MAL, both
required the simultaneous presence of a photosensitizer, small molecules of low molecular weight which easily
light and oxygen inside the diseased tissue. In recent penetrate abnormal epidermis overlying skin tumours,
years, PDT has gained worldwide popularity, first as an were significant milestones in the development of PDT
experimental therapy, then as a primary or palliative in dermatology (1).
therapy for many human cancers. Mainly porphyrins, The most interesting aspect of those porphyrin
chlorin derivatives or phthalocyanines have been studied precursors is their tumour selectivity. After topical
so far for primary or adjuvant cancer therapy (2). application, both ALA and MAL are mainly taken up
However, for dermatological purposes, only haemato- by cells of epithelial origin and are converted into
porphyrin derivatives like porfimer sodium (PhotofrinH) photosensitizing porphyrins (8). MAL has shown a
or protoporphyrin IX (PPIX)-inducing precursors like higher selectivity for tumour cells compared with ALA,

# 2005 Taylor & Francis. ISSN 0001-5555 Acta Derm Venereol 85

DOI: 10.1080/00015550510044136
484 R-M. Szeimies et al.

explained by a different mechanism of cellular uptake as treatments or tissue preparation (debulking) prior to
a result of an increased lipophilic structure. Unaffected PDT (18–20).
adjacent epidermis and mesenchymal cells, like fibro- There is no difference regarding the profile of light
blasts, show a much less pronounced porphyrin necessary for a successful ALA- or MAL-PDT, and
production, thus leading to a high ratio between tumour both laser and incoherent light sources can be used.
and surrounding tissue (9). This phenomenon enables Even pulsed laser light sources matching one of the Q-
then both selective detection of lesions (fluorescence bands at 585 nm have been evaluated with equal results
detection) and selective destruction with minimal harm compared to an incoherent light source in the treatment
to the surrounding tissue when the consecutive illumina- of AK (21). Also the use of a long-pulsed dye laser at
tion is performed. 595 nm seems to be effective for the same indication
Currently in Europe the only photosensitizer (22). However, the costs for purchasing and mainte-
approved in dermatology is methyl aminolevulinate nance of these laser systems are substantially high.
(MAL, MetvixH, Photocure AS, Oslo, Norway, and The gold standards in topical PDT are light sources
Galderma SA, Paris, France). MetvixH is approved for with wide illumination fields which accomplish the
PDT of superficial and nodular basal cell carcinoma simultaneous illumination of larger areas, which is often
(BCC) and actinic keratoses (AK) in combination with needed in AK or Bowen’s disease. Here incoherent light
red light. In the USA MetvixiaH, in combination with sources are preferred, either lamps (e.g. PDT 1200L,
red light, and LevulanH Kerastick2 (DUSA, Waldmann Medizintechnik, Villingen-Schwenningen,
Wilmington, MA, USA), containing 5-ALA hydro- Germany) or LEDs (light emitting diodes) (e.g.
chloride, in combination with blue light, are approved Aktilite2, Galderma or Omnilux2, Waldmann), which
for PDT of AK (2). The 5-ALA-based photosensitizers match the absorption maxima of the ALA- or MAL-
are not photoactive themselves, but show a preferential induced porphyrins (5, 16, 23–25). For tissue destruction
intracellular accumulation in the tumour cells and are a light dose – using broad-spectrum red light (580–
metabolized by the haem biosynthesis into photosensi- 700 nm) – of 100–150 J/cm2 (100–200 mW/cm2) is
tizing porphyrins (8–11). If no surface illumination is chosen. For the more narrow emission spectra of the
given, PPIX is metabolized to the photodynamically LED systems (bandwidth approximately 30–40 nm) the
inactive haem within the next 24–48 h (3). values given are significantly lower (37–50 J/cm2).
Meso-tetrahydroxyphenylchlorin (mTHPC) or the However, therapeutic efficacy of broad-spectrum and
benzoporphyrin derivative monoacid A ring (vertepor- narrow-spectrum lamps has not been compared yet. In
fin) are other photosensitizers that have been applied any case, the light intensity should not exceed
systemically for the treatment of BCC and Bowen’s 200 mW/cm2 so as to avoid hyperthermic effects (16,
disease (12, 13). In contrast to HPD, those second 23). During illumination, both the patient and clinic
generation photosensitizers show only limited cutaneous staff should be wearing protective goggles to avoid the
phototoxicity. risk of eye damage (26).

LIGHT SOURCES MECHANISM OF ACTION

After the preferential synthesis of porphyrins inside the Following activation of a photosensitizer with light of
diseased tissue, the resulting photosensitizers can be the appropriate wavelength, reactive oxygen species
activated by light. The porphyrins or related photo- (ROS), in particular singlet oxygen, are generated.
sensitizers exhibit a very typical absorption spectrum Depending on the amount and localization in the target
with a high peak at approximately 405 nm, the so-called tissue these ROS modify either cellular functions or
Soret-band. Visible blue light matching this band induce cell death by necrosis or apoptosis (2, 6, 10).
therefore can be used in combination with ALA for Interestingly, so far, apart from two case reports with
AK (14). Several so called Q-bands also exist, the last possible coincidence, no further reports on the carcino-
having an absorption peak at 635 nm. Although the genic potential of ALA/MAL-PDT have been published
peak is much smaller than that at 405 nm, this (11). Moreover, in a recent study even long-term topical
wavelength is predominantly used for illumination as application of ALA and subsequent illumination with
light in the red spectrum shows the best tissue blue light in a hairless mouse model did not induce skin
penetration (15, 16). It has been shown in a comparative tumours (27). As proliferating, relatively iron-deficient
trial that light at shorter wavelengths is less effective in tumour cells of epithelial origin are preferentially
the treatment of Bowen’s disease at a theoretically sensitized by ALA or MAL, tissue damage is mostly
equivalent dose; therefore only the use of red light is restricted to the tumour. This leads to a low risk of
recommended for PDT of skin tumours (10, 17). With damage to the surrounding tissue resulting in an
red light, non-melanoma skin cancer up to a thickness of excellent cosmesis (11). In contrast to systemic photo-
2–3 mm can be treated, thicker lesions require multiple sensitizers, where vascular breakdown of the tumour

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 Photodynamic therapy for non-melanoma skin cancer 485

microcirculation is one of the main mechanisms of administration of analgesics is useful (34). Pain percep-
action of PDT, topical PDT has minimal effect on tion can also be reduced by concurrent cold air analgesia
tumour vasculature (10). which has been shown to improve the tolerability of
ALA/MAL-PDT (35). The application of local anaes-
thetics like eutectic mixtures of lidocaine/prilocaine
FLUORESCENCE DETECTION
prior to irradiation is generally not recommended.
The aforementioned tissue selectivity of porphyrin There is the possibility of interaction during the
induction can also be exploited for diagnostic incubation period of ALA/MAL as the high pH of the
purposes: after topical or systemic application, por- anaesthetic might chemically inactivate the photosensi-
phyrin-containing tissue can be illuminated with blue tizing drug. After light exposure, localized erythema and
light at the Soret-band, thus leading to the emission oedema in the treated area are usually seen, followed by
of pink fluorescent light. The high tumour to surround- a dry necrosis sharply restricted to the tumour-bearing
ing tissue ratio then enables the delineation of the areas over the next few days. After 10–21 days, formed
tumour (9, 28). crusts come off and complete re-epithelialization is
This procedure, called fluorescence detection (FD), observed. During this phase, most patients report only
can enable the dermatologist to perform either a guided slight discomfort.
biopsy or a controlled and complete resection of
Due to the selective photosensitization, restricted
tumour, sparing unaffected tissue. By using a commer-
predominantly to cells of epithelial origin with sparing
cial digital CCD camera system, together with digital
of fibroblasts or dermal fibres, usually no scarring or
imaging, the contrast of the acquired fluorescence
ulceration is observed clinically (10, 11, 19). Pigmentary
images can be enhanced significantly and allows the
changes are also rare and only of temporary duration.
determination of a threshold, which can be utilized
Irreversible alopecia has not yet been observed in the
either for a directed biopsy or for preoperative planning
vast majority of the treated patients; however, due to the
when Moh’s surgery is scheduled (29). Moreover, FD is
concomitant sensitization of pilosebaceous units, this
probably a helpful tool to prove the efficacy of PDT. At
potential risk should be considered (10, 11, 36).
present, the routine employment of such systems is being
Apart from patients with a known history of
assessed in prospective trials.
porphyrias or allergic reactions to the active ingredients
of the applied sensitizers, no severe limitations to
TOPICAL PDT – PRACTICAL ASPECTS performance of ALA/MAL-PDT are known (37).
Prior to incubation with the photosensitizer in hyper- The PDT procedure is repeatable and applicable
keratotic lesions, keratolysis or gentle abrasion should even in areas with prior exposure to ionizing irradiation
be performed with an ointment or wet cloth or by slight, (38).
non-bleeding curettage (19, 20, 26, 30). Hyperkeratosis
is the reason for a poor response in AK localized on the THERAPEUTIC APPLICATIONS
hands (10). To date, ALA as hydrochloride has been
applied in custom-made formulations, either creams or Approved indications for MAL in most European
gels, sometimes with penetration enhancers, e.g. DMSO countries, New Zealand and Australia are AK and
in a concentration of up to 20%. In the USA ALA is nodular or superficial BCC. Recently, MAL also
commercialized as LevulanH Kerastick2 with an incu- received an approval in the US for AK where it will
bation time of 14–18 h. The most widely available be marketed under the name MetvixiaH. In addition,
commercial product since June 2001 has been MAL, treatment of Bowen’s disease is also indicated for
available as MetvixH. PDT with ALA/MAL-induced porphyrins as recom-
ALA preparations are usually applied to the lesions mended by evidence-based guidelines (11). However,
with little overlap to the surrounding tissue for 4–6 h for treatment of single lesions a variety of efficient
prior to illumination under occlusion and with a light alternatives exist, e.g. cryotherapy, surgery or drugs like
protective dressing or clothing (10). For the MAL 5-fluorouracil (5-FU), imiquimod or diclofenac-sodium.
ointment the procedure is standardized and a shorter In contrast, for multiple lesions PDT has the potential
incubation time of 3 h is sufficient due to preferential of being a first-line therapy, in particular for AK of the
uptake and higher selectivity (31, 32). The entire area is scalp and face or in cases of basal cell naevus syndrome
then covered with a foil to allow for better penetration. (2). In the following three sections, recent clinical trials
Stinging pain and/or a burning sensation can be published in peer-reviewed journals on the use of ALA/
experienced during PDT, but are usually restricted to MAL-PDT for a variety of epithelial cancers will be
the period of illumination and a couple of hours presented. In respect of limited data on recurrence rates
thereafter (11). A recent publication has shown that in the long-term follow-up, especially for BCC, pub-
MAL-PDT induces less pain than ALA (33). In lished abstracts on follow-up data of those trials were
some cases of PDT with extensive treatment fields, also considered.

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486 R-M. Szeimies et al.

Basal cell carcinoma Solèr and colleagues (19) studied the long-term
effects of MAL-PDT in 59 patients with 350 BCC.
ALA/MAL-PDT for BCC has been studied extensively
Nodular tumours were debulked before PDT and MAL
in recent years in a variety of surveys (3, 10, 19, 20, 39–
(160 mg/g) was applied to all tumours for 24 h or 3 h
46). The weighted average complete clearance rates,
prior to irradiation with a broadband halogen light
after follow-up periods varying between 3 and 36
source (50–200 J/cm2). Patients were followed for 2–4
months, were 87% in 12 studies treating 826 superficial
years (mean 35 months). Overall cure rate was 79% with
BCC and 53% in 208 nodular BCC (3, 11). Available
a recurrence rate of 11% at 35 months and cosmetic
compiled data from other trials have shown an average outcome was excellent or good in 98% of the completely
of 87% for superficial BCC, and 71% for nodular BCC responding lesions (19).
(2) (see Table I). In an open, uncontrolled, prospective, multicentre
In order to ameliorate poor outcome after PDT of trial both patients with superficial and/or nodular BCC
thicker BCC lesions, Thissen et al. (20) treated 23 who were at risk of complications, poor cosmetic
patients with 24 nodular BCC once with ALA-PDT outcome, disfigurement and/or recurrence using con-
(incoherent red light; 100 mW/cm2, 120 J/cm2) 3 weeks ventional therapy were studied. Ninety-four patients
after prior debulking of the BCCs. Three months later were treated with a single cycle of MAL-PDT involving
the former tumour sites were excised and histopatho- two treatment sessions 1 week apart, and followed up at
logically evaluated for residual tumour. Twenty-two 3 months, at which time non-responders were retreated.
(92%) of the 24 nodular BCC showed a complete The clinical lesion remission rate after 3 months was
response, both clinically and histologically. 92% for superficial BCC and 87% for nodular BCC.
In a prospective phase III trial comparing ALA-PDT Histological cure rate at this time point was 85% in
with cryosurgery, Wang et al. (42) included 88 super- superficial BCC and 75% in nodular BCC (95%
ficial and nodular BCC. Recruited individuals were only confidence interval, 70–85%). At 36 months after
allowed to have one lesion to be included in the trial. A treatment, the overall lesion recurrence rate was 23%
20% ALA/water-in-oil cream was applied for 6 h under in this difficult to treat population (39).
an occlusive dressing, followed by illumination with a In a prospective, open-label, comparative, multicentre
laser at 635 nm (80 mW/cm2, 60 J/cm2). In the cryosur- phase III study Basset-Seguin and colleagues treated a
gery arm, lesions were treated with liquid nitrogen by total of 118 patients with histologically confirmed
the open spray technique, using two freeze-thaw cycles superficial BCC. They were randomized to either cryo-
of 25–30 s each. After 3 months, the clinical recurrence therapy (n558) or MAL-PDT (n560; 3 h application
rates were only 5% for ALA-PDT and 13% for time, red light (570–670 nm) total light dose 75 J/cm2).
cryosurgery. However, on analysing punch biopsies a Lesion response and cosmetic outcome of lesions
recurrence rates of 25% in the PDT group and 15% in clinically in complete response were monitored con-
the cryosurgery group were determined, but the results tinuously. Data from 107 patients have been analysed so
were not statistically significant (pw0.05, Fisher’s exact far after 36 months, the recurrence rates were 22% for
test). Besides better cosmetic outcome, healing time was MAL-PDT and 19% for cryotherapy, which was not a
also shorter in the PDT-treated group. statistically significant difference (43). It is important to

Table I. Summary of results of clinical studies using topical 5-aminolevulinic acid (ALA) or methyl aminolevulinate photodynamic
therapy (MAL-PDT) for the treatment of basal cell carcinoma (BCC)

Number Lesion
Study Indication/procedure Sensitizer of lesions recurrence rates Follow-up

Thissen 2000 (20) Nodular BCC (debulking 3 weeks ALA 24 … 3 months

prior to PDT) (histological control)
Wang 2001 (42) Superficial and nodular BCC ALA 44 13% 12 months
Solèr 2001 (19) Superficial and nodular BCC MAL 350 11% 24–48 months
(debulking of nodular tumours (mean of 35 months)
prior to PDT)
Horn 2003 (39) ‘Difficult-to-treat’ superficial and MAL 49 23% 36 months
nodular BCC
Vincuillo 2005 (45) ‘Difficult-to-treat’ superficial and MAL 148 24% 24 months
nodular BCC
Rhodes 2004 (41) Nodular BCC MAL 53 10% (pw0.05) 36 months
Basset-Seguin 2004 (43) Superficial BCC MAL 55 22% (pw0.05) 36 months
(with 1 MAL-PDT
treatment session)

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 Photodynamic therapy for non-melanoma skin cancer 487

note that two MAL-PDT treatment sessions are ALA-PDT can also be used for adjuvant therapy in
indicated in the EU labelling for BCC and in this study combination with Mohs’ surgery, as reported recently
patients were treated with one MAL-PDT session, by Kuijpers et al. (46). In four patients, who underwent
repeated for patients with non-complete response at 3 Mohs’ micrographic surgery for extensive BCC, first the
months. central infiltrating tumour part was excised. After re-
In another European multicentre, open, randomized epithelialization, ALA-PDT of the surrounding tumour
trial, MAL-PDT for nodular BCC was compared with rims (2–5 cm) bearing remaining superficial tumour
surgery. A total of 101 patients was included and they parts was performed. This led to a complete remission of
received either two courses of PDT, 7 days apart the tumours with excellent clinical and cosmetic results
(75 J/cm2 red light) or surgical excision. The primary (follow-up period527 months) (46).
end point of this trial was lesion clearance (assessed
clinically) 3 months after treatment. The 3-month cure Actinic keratoses
rate was similar with MAL-PDT or surgery (91% vs The efficacy of ALA-PDT has been observed in 6 open
98%), the 24-month lesion recurrence rate was 10% with studies of 323 AK situated on the face and scalp in
MAL and 2% with surgery (estimated difference 95% Caucasian populations. Clearance rates ranged from 71
CI, 21 to 22). The cosmetic result was rated good/ to 100% after just a single treatment (11, 47). For
excellent in 85% of the patients receiving PDT vs 33% illumination purposes, both red (635 nm) or blue light
with surgery (41). (417 nm) have been used (14, 47). Green light may also
In a comparative trial in Australia, MAL-PDT for be effective, but the user should always bear in mind
nodular BCC was compared to placebo. Lesions from that non-red light should not be used for indications
66 patients were treated with two sessions of either other than AK due to the lack of tissue penetration (10).
placebo or MAL-PDT in a randomized, double-blind In a European, multicentre, randomized prospective
controlled study. In cases where there was no complete study, MAL-PDT was compared to cryosurgery in the
response 3 months after initial treatment, lesions were treatment of AK. A total of 193 patients (95%) with 699
excised. After 6 months, histologically confirmed lesions completed the trial. Patients received either a
complete remission rate was 73% for MAL-PDT single treatment with MAL-PDT (repeated after 1 week
compared to 21% for placebo (31). in 8% of cases) or a double freeze-thaw course of liquid
In the USA, a multicentre, randomized, double-blind, nitrogen cryosurgery. MAL was applied for 3 h after
placebo-controlled trial comparing MAL-PDT and slight lesion preparation, followed by illumination with
placebo-PDT in 65 patients with nodular BCC was broad-spectrum red light (75 J/cm2). A follow-up visit
performed. Forty-one BCC in 33 subjects received 2 was performed 3 months post treatment. The efficacy
cycles of MAL-PDT; 39 BCCs in 32 subjects received 2 for MAL-PDT (single application) was 69% (95% CI,
cycles of placebo-cream PDT. Prior to PDT, surface 64–74%) vs 75% (95% CI, 70–80%) for cryosurgery,
debridement was performed. After 3 months, lesions which was not statistically significant. Thin lesions on
with no clinical response were excised and lesions with the scalp had the highest response rates (80% and 82%
partial response were retreated. Six months after the last for PDT and cryosurgery, respectively). Cosmetic out-
treatment, BCC manifesting complete clinical response come, as judged by the investigator, was superior for
were excised to determine complete histological MAL-PDT (96% vs 81%, p50.035) (32).
response. The overall complete histological response A comparable trial was conducted in Australia. In
was 79% for MAL-PDT, compared with 33% for this study MAL-PDT was used as a dual cycle, with two
placebo-PDT, which was significantly superior treatment sessions, 1 week apart. PDT was compared to
(pv0.001) (31, 44). a single course of cryosurgery or placebo in 204 patients.
In a prospective, multicentre, non-comparative study Lesion response was also assessed after 3 months. A
in Australia, MAL-PDT was used for BCC defined as significantly higher complete remission rate with MAL-
‘difficult-to-treat’, i.e. large lesions, in the H-zone, or in PDT was observed (91% vs 68% with cryosurgery and
patients at high risk of surgical complications. Ninety- 30% with placebo). Lesion response was statistically
five patients with 148 lesions were included in the per significantly higher for MAL-PDT compared with both
protocol analysis. The histologically confirmed lesion placebo PDT (pv0.001) and cryotherapy (pv0.001).
complete response rate at 3 months was 89% (131 of The cosmetic result was rated excellent in 81% of MAL-
148). At 24 months, a cumulative treatment failure rate PDT patients vs 51% treated with cryosurgery as
of 24% (36 of 148) was observed. Overall cosmetic assessed by the investigator (pv0.001) or 76% vs 56%
outcome was judged as excellent or good in 84% of as assessed by the patient (p50.013) (48).
patients at 24 months. Interestingly, lesions located on Finally, a multicentre, randomized, double-blind,
the face/scalp region showed a significantly lower lesion placebo-controlled study with two MAL-PDT
complete response rate than that of lesions on the trunk/ cycles was performed in 80 patients with AK in the
neck (at 24 months, 54% vs 88%, p50.009) (45). USA. PDT treatment parameters were similar to the

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488 R-M. Szeimies et al.

above-mentioned trials. Assessment after 3 months of 33). After 1 year of follow-up, further recurrences
revealed a complete lesion response rate of 89% for reduced the complete clinical clearance rates to 82% and
MAL-PDT vs 38% for placebo and a patient complete 42%, respectively (50).
response rate of 82% for MAL-PDT (95% CI, 67–93%) MAL-PDT has recently been studied in the largest
vs 21% (95% CI, 21–37%) for placebo (p50.001). An existing study in the treatment of Bowen’s disease. In
excellent or good cosmetic outcome was reported in 97% this European multicentre (40 centres) comparative
of MAL-treated patients (49). randomized controlled study performed in a total of
Also for ALA-PDT a randomized, placebo- 225 patients with 275 lesions, MAL-PDT induced a
controlled, uneven-parallel-group study was published complete response in 93% of lesions compared to 86%
recently. In 243 patients clinical response, based on with cryotherapy and 83% with 5-FU. At 12 months the
lesion clearing, was assessed by weeks 8 and 12. Patients overall lesion cure rates were 74% with MAL-PDT
were randomized to receive either vehicle or ALA compared to 65% and 62% with cryotherapy and 5-FU
(LevulanH Kerastick2), followed within 14–18 h by (51).
illumination with visible blue light. Complete response
rates for ALA-PDT patients with >75% of the treated
CONCLUSION
lesions clearing at weeks 8 and 12 were 77% and 89%,
respectively. In the placebo group, clearing rates were The developments in PDT are continuously advancing.
18% and 13% (pv0.001 at weeks 8 and 12). The 12-week At present, ample data exist which demonstrate the
clearing rates included 30% of patients who received a usefulness of PDT for the treatment of cutaneous
second ALA-PDT course. Moderate to severe discom- malignancies and benign conditions (6). So far the
fort during illumination was reported by at least 90% of proven advantages of PDT include comparable clinical
patients; however, only 3% of patients required dis- outcome to standard treatments, the simultaneous
continuation of therapy (14). treatment of multiple tumours and incipient lesions,
For the purpose of lowering the amount of side effects relatively short healing times, tumour control in immuno-
of ALA-PDT, shorter incubation periods (1–3 h), in compromised patients (e.g. transplant recipients),
conjunction with pre-treatment with 40% urea in order high patient tolerance and an excellent cosmesis. Cost-
to enhance ALA penetration and the use of topical 3% effectiveness analysis indicates that with relatively low
lidocaine hydrochloride to decrease discomfort were costs for permanent equipment, topical ALA/MAL-PDT
also evaluated. One and 5 months after therapy in 18 is probably no more expensive than conventional therapy
patients with at least 4 non-hypertrophic AK, an up to when its lower side effect profile is considered (11).
90% reduction of lesions in the target area was observed. ALA/MAL-PDT has been rated to compete with
No difference was seen between the three incubation concurrent standard medical therapies for indications
periods, nor did pre-treatment with urea or lidocaine like AK, BCC and Bowen’s disease. However, as PDT is
have a positive influence on the therapeutic outcome a treatment which, unlike surgery, does not provide
(p50.99) or the development of pain during irradiation histological control, lesions to be treated should be
(p50.65) (34). selected very carefully to exclude unresponsiveness (as in
morpheic BCC) or inappropriate results (tumour
Bowen’s disease and initial squamous cell carcinoma thickness exceeding 3 mm). Especially for BCC, a final
judgement on efficacy is still pending since the 5-year
Topical PDT using 20% ALA has been assessed follow-up data on recurrence rates are not yet available.
extensively in Bowen’s disease with more than 14 open
However, recently reported 36-month data show
and 3 randomized comparison studies (11, 17, 40, 50).
encouraging results with recurrence rates equivalent to
Cure rates reported so far are the best for all epithelial
that of currently standard therapies.
cancers or precursors (up to 100%). In a recent study by
Salim et al. (50), ALA-PDT was compared to topical 5-
FU. In this two-centre, randomized, phase III trial 40 ACKNOWLEDGEMENTS
patients with 1 to 3 lesions of previously untreated, Drs Szeimies, Morton, Sidoroff and Braathen have received
histologically proven Bowen’s disease received either support from Photocure AS for performing clinical trials. Drs
PDT or 5-FU. ALA 20% in an oil/water emulsion was Szeimies, Morton and Braathen have received speakers’
applied 4 h prior to illumination with an incoherent honoraria from Galderma SA. Dr Szeimies is also a consultant
light source (Paterson lamp, Phototherapeutics, UK; for other companies that have and are developing treatments
for AK.
lem5630¡15 nm; 50–90 mW/cm2, 100 J/cm2). Treat-
ment with 5-FU was once daily in week 1 and then twice
daily during weeks 2–4. At first follow-up at week 6,
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