10.5826/dpc.1304a291
Introduction: Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized skin.
Objectives: Our review aims to present the up-to-date literature on skin field cancerization using PDT employing different topical photosensitizers, modified light delivery protocols and combination treatments to obtain excellent efficacy and safety in everyday clinical practice.
Methods: We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library, Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND photodynamic therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness OR pain OR tolerability) for studies published until February 2023.
Results: Advantages of PDT compared to the other field treatments, including imiquimod, 5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment duration. Alternate illumination methods have also been investigated, including daylight as a light source. Pretreating the affected area may enhance photosensitizer absorption leading to better therapeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ transplant recipients.
Conclusion: This review provides a thorough display of the field of PDT on cancerized skin, which will facilitate physicians in applying PDT more efficiently and intuitively.
text/xml
2160-9381
3509
en
Eleni Sotiriou
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
AK
Photodynamic Therapy for Field Cancerization in the Skin: Where Do We Stand?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-10-31
2023-05-05
2023-10-31
2024-01-16
e2023291
Dermatol Pract Concept
Introduction: Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized skin.
Objectives: Our review aims to present the up-to-date literature on skin field cancerization using PDT employing different topical photosensitizers, modified light delivery protocols and combination treatments to obtain excellent efficacy and safety in everyday clinical practice.
Methods: We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library, Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND photodynamic therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness OR pain OR tolerability) for studies published until February 2023.
Results: Advantages of PDT compared to the other field treatments, including imiquimod, 5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment duration. Alternate illumination methods have also been investigated, including daylight as a light source. Pretreating the affected area may enhance photosensitizer absorption leading to better therapeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ transplant recipients.
Conclusion: This review provides a thorough display of the field of PDT on cancerized skin, which will facilitate physicians in applying PDT more efficiently and intuitively.
Eleni Sotiriou
2023/10/31
10.5826/dpc.1304a291
e2023291
First Department of Dermatology and Venereology, Aristotle University of Thessaloniki, Greece
2160-9381
AK
en
e2023291
Piacquadio, D.; Houlihan, A.; Ferdon, M.B.; Berg, J.E.; Marcus, S.L. A Randomized Trial of Broad Area ALA-PDT for Field Cancerization Mitigation in High-Risk Patients. J Drugs Dermatol 2020, 19, 452-458.
Photodynamic Therapy for Field Cancerization in the Skin: Where Do We Stand?
https://dpcj.org/index.php/dpc/article/download/3509/2397
       Photodynamic Therapy for Field Cancerization
             in the Skin: Where Do We Stand?
 Katerina Bakirtzi1, Ilias Papadimitriou1, Efstratios Vakirlis1, Aimilios Lallas1, Eleni Sotiriou1


1 First Department of Dermatology and Venereology, Aristotle University of Thessaloniki, Thessaloniki, Greece



Key words: actinic keratosis, photodynamic therapy, skin field cancerization
Citation: Bakirtzi K, Papadimitriou I, Vakirlis E, Lallas A, Sotiriou E. Photodynamic Therapy for Field Cancerization in the Skin: Where Do
We Stand? Dermatol Pract Concept. 2023;13(4):e2023291. DOI: https://doi.org/10.5826/dpc.1304a291
Accepted: May 29, 2023; Published: October 2023
Copyright: ©2023 Bakirtzi et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Bakirtzi Katerina, MSc, Aristotle University of Thessaloniki, Delfon 124, Thessaloniki, P.O. 54643, Greece.
Email: bakirtzicatherine@hotmail.com




  ABSTRACT             Introduction: Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of
                       multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized
                       skin.
                       Objectives: Our review aims to present the up-to-date literature on skin field cancerization using
                       PDT employing different topical photosensitizers, modified light delivery protocols and combination
                       treatments to obtain excellent efficacy and safety in everyday clinical practice.
                       Methods: We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library,
                       Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND ­photodynamic
                       therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness
                       OR pain OR tolerability) for studies published until February 2023.
                       Results: Advantages of PDT compared to the other field treatments, including imiquimod,
                       5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater
                       patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment
                       duration. Alternate illumination methods have also been investigated, including daylight as a light
                       source. Pretreating the affected area may enhance photosensitizer absorption leading to better ther-
                       apeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT
                       to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive
                       treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ
                       transplant recipients.
                       Conclusions: This review provides a thorough display of the field of PDT on cancerized skin, which
                       will facilitate physicians in applying PDT more efficiently and intuitively.




Review | Dermatol Pract Concept. 2023;13(4):e2023291                                                                                     1
Introduction                                                       its accumulation because of cells distorted uptake. The re-
                                                                   action of light and photosensitizing compounds generates
The permutation of light and chemical agents for managing          active oxygen species, which stimulate the apoptotic process
disorders has its origins in ancient times when the ancient        of skin cancer cells [10]. Another novel modality, daylight
Egyptians and Indians first utilized psoralen to cure the de-      PDT (DL-PDT), gains ground for treating AKs as more ap-
pigmentation of vitiligo under sun exposure [1,2]. In 1903,        pealing, equally beneficial in many cases, well-tolerated, and
Niels Finsen won Nobel Prize in Physiology or Medicine for         convenient. It is irrelevant to light-emitting diode (LED) light
his achievements in this niche. The same year, Von Tappeiner       compared to conventional PDT (C-PDT) since it entails di-
combined light and organic dye eosin for skin cancer treat-        rect exposure to daylight [11].
ment giving this therapy the name “photodynamic action”,
which was the ancestor of modern photodynamic therapy
(PDT) [1].                                                         Objectives
    Since the skin is the body organ exposed to the environ-
                                                                   Given the rapid expansion of PDT and skin cancer in the
ment and, thereby, to light, dermatology is an area with a
                                                                   latest years, reviewing its present application in field can-
plethora of prospects for PDT application, from acne treat-
                                                                   cerization and condensing future research trends would
ment to skin cancer [3,4]. Skin cancer is generally subgrouped
                                                                   be conducive for healthcare professionals. Building on this
into melanoma skin cancer (MSC) and non-melanoma skin
                                                                   concept, we gleaned from the international literature the rel-
cancer (NMSC). MSCs are highly malignant with metastasis
                                                                   evant studies and included any available information that
potential but are not indicated of PDT. NMSC is universally
                                                                   would promote the clinical practice and assist investigators
the most common variant, with basal cell carcinoma (BCC)
                                                                   in swiftly grasp the progress trends in the field.
accounting for 75%-80% of all cases, followed by squamous
cell carcinoma (SCC) [5]. Actinic keratoses (AKs) are con-
sidered a precancerous type of cutaneous SCC, with a con-          Methods
siderably varying risk of malignant transformation assessed
between 0.025%-16%. Male sex, older age, and Fitzpatrick           For this review, we searched the following databases:
I or II phototype skin are predisposing risk factors for AK        PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct,
formation, mainly in patients with chronic exposure to ultra-      Cochrane library, Research Gate and Google Scholar. The
violet (UVB) radiation and in areas with extensive sunlight        search terms were [(aminolevulinic acid OR aminolevuli-
exposure such as the face, the hairless scalp, neck and the        nate) AND photodynamic therapy] with (field-directed OR
dorsal extremities [6].                                            field cancerization, (actinic keratosis), and (efficacy OR ef-
    The concept of field cancerization was first introduced        fectiveness OR pain OR tolerability). Studies were included
by Slaughter et al in 1953 when they detected histologically       from inception to February 2023. We included randomized
atypical cells around oral squamous cell carcinoma [7]. Cur-       clinical trials, prospective studies, and randomized com-
rently, the term skin field cancerization is applied to the skin   parison studies involving patients with skin field canceriza-
area clinically with or adjoining to AK on the ground of           tion that had undergone photodynamic therapy, including
photodamaged skin. For the diagnosis, a minimum of two             MAL-PDT, ALA-PDT, C-PDT, DL-PDT, ablative fractional
of the following signs should be present: telangiectasia, at-      laser resurfacing (AFXL)-PDT, and MAL-DL-PDT.
rophy, pigmentation disorders, and “sandpaper” texture. It            Data extraction was performed individually for each
is not yet specified whether a visible AK is required for the      intervention. The pertinent information obtained from
definition [8]. Nevertheless, field-directed treatment is highly   each study was: the first author; year of publication; type
recommended for patients with extensive AKs in large skin          of study; type of PDT intervention; the number of patients;
areas. For this purpose, various modalities are available, in-     demographics of patients; skin phototype; and treatment
cluding surgical excision, cryotherapy, curettage, PDT, and        outcomes. The search included exclusively English-language
topical agents, such as 5-fluorouracil, imiquimod, ingenol         academic papers. The reference list of the shortlisted articles
mebutate, and diclofenac [9].                                      has also been examined for supplementary studies. This re-
    Photodynamic therapy is currently considered an effi-          view paper is based on formerly conducted studies and does
cient method for AK and field cancerization [3]. Its mode          not encompass any novel trials with human participants or
of action relies on visible light that interacts with photosen-    animals conducted by any of the authors.
sitizing chemical agents, specifically the 5-aminolevulinic           The study has been designed, and the results have been
acid ALA and methyl-aminolevulinate MAL. Both prodrugs             described as per the Preferred Reporting Items for Systematic
promote protoporphyrin IX (PpIX) production and induce             Reviews and Meta-Analyses (PRISMA) statement.




2                                                                             Review | Dermatol Pract Concept. 2023;13(4):e2023291
                          Identificationt
                                            Records identified from:               Records removed before
                                              Medline, Embase,                     screening:
                                              Cochrane (n = 296)                      Duplicate records
                                              Other sources (n = 6)                   removed (n = 0)




                                            Records screened                       Records excluded
                                            (n = 302)                              (n = 21)



                                            Reports sought for                     Reports not retrieved
                                            retrieval
                          Screening




                                                                                   (n = 126)
                                            (n = 281)


                                            Reports assessed for                   Reports excluded after
                                            eligibility                            quality assessement (n =
                                            (n = 155)                              122)
                              Include




                                            Studies included in review
                                            (n = 33)

                           Figure 1. Flow chart of search results and study selection.




                Figure 2. Scientific papers for photodynamic therapy in skin field cancerization published until 2023.



   Our literature search yielded 143 studies. After excluding            Results
case reports, systematic reviews, duplicate studies, studies
that did not present any relevant data or did not conform to             The annual timeline analysis illustrates an overall escalating
the inclusion or exclusion criteria, and studies that referred           trend in the number of publications, which reveals that PDT
to individual lesions and not to field cancerized skin and               on skin field cancerization attracts the increasing interest of
treatment other than photodynamic therapy, we ended up                   the dermatological community (Figure 2). Up to 2023, a to-
with 33 studies (Figure 1).                                              tal of 193 articles and reviews were linked to PDT in skin




Review | Dermatol Pract Concept. 2023;13(4):e2023291                                                                                  3
cancer. Skin field cancerization is distinguished by the pres-    cost-effective [21]. A phase III multicenter, randomized,
ence of premalignant and, potentially, cancerous lesions over     double-blind, vehicle-controlled trial examined the efficacy
a limited skin area [9]. In everyday clinical practice, such      of field-directed treatment with 10% BF-200 ALA gel and
lesions may not be readily noticeable, or an indication of less   red-light PDT in 87 patients with mild-to-moderate AKs
extensive and severe lesions could be observed. It has been       of the face and/or scalp. After 12 weeks of the PDT treat-
well documented that sunlight is of key importance for the        ment, field-directed PDT obtained complete lesion clearance
early development of AK since it promotes mutations in the        in 91% of BF-200 ALA-treated patients compared to 22%
p53 tumor suppression gene [12]. These mutations are not          of vehicle-treated patients [20]. A randomized, double-blind
limited to visible lesions but are also present in sun-exposed    trial compared the efficacy and safety of ALA- and MAL-
skin, where subclinical lesions may occur [13]. Therefore,        PDT for the treatment of cancerized skin on the scalp. It con-
field-cancerized skin displays identical genetic modifications    cluded that both therapies led to a noteworthy decrease in
observed in the malignant lesions. To this extent, treating       scalp AKs without one overpowering the other. Nevertheless,
such lesions is crucial for malignant inhibition, and photo-      the authors noted that ALA-PDT seemed more painful than
dynamic therapy plays a significant role to this end.             MAL-PDT in extensive scalp premalignant lesions [22]. One
    In the absence of a robust way to reliably detect subclin-    of the earliest trials in the field showed a substantial delay
ical damage of the skin or AKs with potential future ma-          in the onset and a reduction in the number of new lesions
lignant transformation, it would be a reasonable approach         when field therapy with ALA-PDT was applied to patients
to treat the entire area of cancerized skin simultaneously        with significant field changes [23]. Relevant results, though,
with the individual lesions. Surgical treatment is not feasi-     were also reported in another similar study where MAL-PDT
ble when an extensive body surface area is involved. On the       was used [24].
other hand, topical therapies are often not preferred at some        When compared to other treatment modalities for
point by patients due to the intense local skin reaction to       skin field cancerization, the lesion-specific clearance for
the drug compound or the lengthy therapeutic course [14].         MAL-PDT was significantly higher than other regimens,
Under these circumstances, PDT could be considered a com-         including ingenol mebutate, diclofenac plus hyaluronate
plementary or alternative treatment to improve the quality        gel, and imiquimod cream. It was also proved that MAL-
of life and anticipate the undesirable evolvement of the pre-     PDT improved all the traits of chronic photodamage in
cancerous lesions.                                                the dermis underlying and adjacent to the AK lesions [25].
    Photodynamic therapy is currently approved for the            Sotiriou et al. also showed that MAL-PDT provides superior
treatment of AK and field cancerized skin in the U.S.A.,          outcomes for the prevention of AK development in patients
Canada, and the European Union, as well as in other               with field changes after 12 months of follow-up [26]. On the
­countries of the world. The histological improvement in field    other hand, in a single-blind randomized trial involving four
cancerization after PDT, expressed by less severe and exten-      Dutch hospitals, a total of 624 patients with at least five AKs
sive keratinocyte atypia, is a fact, while the remarkable rise    within an area of 25 to 100 cm2 on the head were recruited
of new collagen deposition and the decrease of solar elastosis    and assigned to either MAL-PDT, imiquimod, ingenol me-
explain the clinical upgrading of photodamaged skin [15].         butate or 5% fluorouracil cream treatment branches. The
Nevertheless, which photosensitizer works best remains            study concluded that, after 12 months post treatment, 5%
inconclusive.                                                     fluorouracil cream surpassed the other three field-directed
    Various randomized controlled trials (RCTs) showed            treatments in efficacy [27].
that MAL- and BF-200 ALA-PDT are sufficiently effective              Based on the conventional ALA-PDT, daylight PDT is
in the complete clearance of treated lesions and cosmetic re-     considered to be more favorable for mild-to-moderate mul-
sults. However, the use of BF-200 ALA seems to be more            tiple precancerous lesions, demonstrating better patient ad-
well-tolerated for patients. Additionally, it yields superior     herence and moderately low variability in results [28-31].
cosmetic outcomes, is less painful, and has a better over-        Although in some cases, for example, when compared to
all therapeutic response rate (RR) compared to MAL-PDT            ingenol mebutate, the clearance rates could be fairly infe-
[16-21]. After twelve weeks, Dirschka et al showed that BF-       rior, patients still prefer D-PDT due to the almost pain-free
200 ALA gel resulted in an almost 20% recurrence rate of          sessions and superior cosmetic results [32]. In a large mul-
AKs in the cancerized field, while the relevant percentage for    ticenter study including 145 patients with various severity
MAL-PDT was 31.6% [19]. In a similar multicenter study,           AK grades (I-III), it was found that lesion response rate was
where authors compared MAL- and BF-200 ALA PDT in                 notably higher in grade I lesions (75.9%) than in grade II
grade I-II AK lesions, BF-200 ALA provided a complete             (61.2%) and grade III (49.1%) lesions, whereas most grade
clearance (CR) rate of nearly 80% and MAL-PDT a little            II and III AKs (86% and 94%, respectively) were in com-
over 70%. At the same time, it was also proved to be more         plete response or downgraded at follow-up [33]. Regarding



4                                                                            Review | Dermatol Pract Concept. 2023;13(4):e2023291
the other PDT modalities, Sotiriou et al indicated that, when      penetration into the skin. The findings favored PDT with
actinic skin field damage is present, the DL-PDT is the treat-     microneedling, as it generated superior cosmetic outcomes
ment of choice among patients, given the comparable effi-          to conventional MAL-PDT for refining photodamaged skin
cacy that it demonstrates when compared to conventional            [38]. Vrani et al used ablative CO2 fractional laser prior to
PDT [30]. One of the first studies carried out on this topic       MAL-PDT treatment with 1-hour incubation in 42 patients
was a phase III, randomized, non-inferiority trial through-        with two mirror cancerized areas of the face or scalp and
out Europe including 96 participants with multiple facial          compared it to conventional PDT [43]. After one year of
or/and scalp AKs. The findings of this study proved that           follow-up, the CO2 fractional laser pretreatment results were
DL-PDT compared with conventional PDT, was equally                 equivalent to those of the conventional PDT while allowing
beneficial, better tolerated and virtually painless, with great    for reduced photosensitizer occlusion time, results that were
patient satisfaction [31]. An intra-individual study includ-       in line with previous studies [43,44]. Pires et al. added acous-
ing fifty patients from six centers in Germany showed that         tic pressure wave ultrasound to the CO2-assisted MAL-PDT
BF- 200 ALA daylight PDT provided better results than the          with a short incubation time for field cancerization. Overall,
vehicle regarding the overall lesion clearance rates (86.0%        638 AKs in 15 patients were treated either with MAL-PDT
versus 32.9%) to CR (67.3% versus 12.2%) on extremities,           alone or with CO2 and acoustic wave ultrasound pretreat-
trunk, and neck. In the meantime, BF-200 ALA DL-PDT                ment. The efficacy of the novel protocol was reported to be
had a lower 12-month total lesion recurrence rate (14.1%           equivalent to the conventional MAL-PDT [42].
versus 27.4%), better cosmetic outcome, and was more                  A randomized split-scalp study by Torezan et al sug-
well-tolerated [34]. In a single-centre, intraindividual, retro-   gested that topical application of calcipotriol could improve
spective study, 19 patients with multiple AKs in the face and      the efficiency of MAL-PDT by 30%, potentially because of
scalp received a combination of ALA-PDT and DL-PDT. The            the elevated PpIX levels [39]. A bilaterally controlled trial of
results were compared to those of the area that underwent          17 patients proved that the pretreatment of skin areas with
only DL-PDT. The outcomes favoured the combined treat-             5-FU for 6 days increased the PpIX levels two- to three-fold
ment regarding the clearance rates of AK lesions, whereas          nearly after MAL-PDT leading to complete clearance by
the pain was reported to be mild to moderate through red           both enhanced photosensitizer accumulation and induction
light illumination [35]. In a multicenter, prospective study       of p53 [41]. With the application of 5-FU prior to PDT field
in Spain, 43 patients with grade I-II AKs on the head ini-         treatment, the relative clearance rates of MAL-PDT increased
tially underwent a session with DL-PDT. After one month            from 45% to 75% at 3 months and from 39% to 67% at
of follow-up, participants without a satisfactory therapeutic      6 months, respectively [41]. A study of 58 patients showed
outcome were randomized either to receive a second session         that vitamin D3 deficiency could be an aggravating factor
of DL-PDT or to be treated with imiquimod. After one year,         regarding the efficacy of PDT, leading to a reduction of ef-
clearance rates were higher in the arm of two sessions of          fectiveness by nearly 20%. Meanwhile, the administration of
DL-PDT monotherapy than that of sequential DL-PDT plus             high-dose vitamin D3 supplementation (10,000 IU daily for
imiquimod (75.2% versus 54.6%, respectively) [36].                 5 or 14 days) before PDT treatment significantly increased
   The combination of PDT with other treatments, such              the response rates from 54.4% to 72.5% [40].
as cryosurgery, laser application, topical regimens or mi-            A recent study tested the efficacy of three physical pre-
croneedling, seems to have a synergic action and enhance           treatment interventions compared to the standard treatment
the therapeutic effect of the respective monotherapy without       using daylight PDT. Forty patients were allocated either to
causing the patients additional discomfort [37-43]. The Mi-        standard DL-PDT, DL-PDT with microneedling, DL-PDT
croneedle Photodynamic Therapy II trial was a randomized,          with CO2 laser or DL-PDT with microdermabrasion. When
single-blinded, split-face controlled, 2-arm clinical study        DL-PDT was combined with physical methods, it provided
where 32 patients with AKs on the face were randomized             better clinical and histologic outcomes. The clearance of
into two incubations arms, either 10- or 20-minute ALA in-         AKs was significantly greater 1 and 3 months post treat-
cubation times, after pretreatment with a microneedle roller       ment with the employment of CO2 laser. Photorejuvenation
or a sham roller. The study results showed that PDT with           was more apparent with CO2 laser and microdermabrasion
microneedling pretreatment at a 20-minute ALA incubation           pretreatment. However, only CO2 laser offered a substan-
time demonstrated equivalent efficacy regarding AK clear-          tial decrease in solar elastosis and an increase in collagen
ance compared to that of a conventional 1-hour ALA in-             type 1 [45]. Especially when it comes to organ-transplant
cubation time. The further benefit of accelerated treatment        recipients with resistant to conventional PDT lesions, add-
was that the procedure was almost painless [37]. In a similar      ing ablative fractional laser along with DL-PDT increases
study, Torezan et al combined microneedling or ablative car-       the clearance rates with excellent tolerability than DL-PDT
bon dioxide lasers with MAL-PDT to increase photosensitizer        and conventional PDT alone [46]. The regimens mentioned



Review | Dermatol Pract Concept. 2023;13(4):e2023291                                                                             5
6
                                                                                                               Table 1. Characteristics of studies and main outcomes.
                                                       +First Author/Year                                                                                                                            Complete Clearance in %
                                                         of publication              Type of study                     Intervention             Number of patients      Time of assessement        (Unless indicated otherwise)
                                                       Dirschka et al, 2013   Two prospective randomized    MAL-PDT versus                      482                    6 and 12 months          MAL-PDT: 36% and BF- 200
                                                                              controlled                    BF-200 ALA                                                                          ALA: 47%
                                                                              phase III trials
                                                       Serra-Guillén et al,   Randomized intraindividual    MAL-PDT versus                      25                     1 month                  MAL-PDT:
                                                       2018                   comparative                   BF-200 ALA                                                                          56% and BF- 200 ALA: 62%
                                                       Neittaanmäki Perttu    Randomized double-blinded     MAL-PDT versus                      13                     3 months                 MALPDT: 74.2% and
                                                       et al, 2014            non-sponsored prospective     BF-200 ALA                                                                          BF-200 ALA: 84.5%
                                                       Dirschka et al,        Randomized intra-individual   DL-MAL-                             52                     12 weeks                 BF-200 ALA DL-PDT: 79.8% and
                                                       2018                   non-inferiority               PDT versus BF-200                                                                   MAL-DL-PDT: 76.5%
                                                                              phase III                     ALA DL-PDT
                                                       Reinhold et al, 2016   Randomized, double-blind,     BF-200 ALA combined with the BF-    55 patients received   3 months with a          BF-200 ALA: 91% and
                                                                              phase III, multicentre        RhodoLED versus placebo             BF-200 ALA, 32         potential of an          placebo: 22%
                                                                                                                                                received placebo       additional PDT session
                                                       Räsänen et al, 2019    Non-sponsored, prospective    BF-200 ALA versus MAL in DL-PDT     69                     12 months                BF-200 ALA DL-PDT: 79.7% and
                                                                              randomized double-blind                                                                                           MAL DL-PDT: 73.5%
                                                                              multicentre
                                                       Moloney et al, 2007    Randomized, double-blind,     MAL-PDT versus ALA-PDT              15                     1 month                  Mean reduction from baseline in AK
                                                                              prospective                                                                                                       counts with ALA-PDT: 6.2 +/- 1.9
                                                                                                                                                                                                and MAL-PDT: 5.6 +/- 3.2
                                                       Apalla et al, 2010     Randomized                    ALA-PDT versus placebo              39                     12 months                ALA-PDT: 64% and placebo: 26%
                                                                              placebo-controlled
                                                       Kleinpenning et al,    Comparative to baseline       MAL-PDT                             14                     3 months                 42.9%
                                                       2010
                                                       Arisi et al, 2020      Randomized, cohort            MAL-PDT, ingenol mebutate gel and   90 patients, 30 in each 90 days                 MAL-PDT: 23.07%,
                                                                                                            diclofenac plus hyaluronate gel     cohort                                          ingenol mebutate: 30% and
                                                                                                                                                                                                diclofenac plus hyaluronate: 14.28%
                                                       Sotiriou et al, 2015   Randomized intraindividual    MAL-PDT versus. Imiquimod 5%        44                     12 months                No statistically significant difference
                                                                              comparison                                                                                                        between the two mirrored fields
                                                                                                                                                                                                regarding the development of new
                                                                                                                                                                                                lesions.




Review | Dermatol Pract Concept. 2023;13(4):e2023291
                                                       +First Author/Year                                                                                                                        Complete Clearance in %
                                                         of publication               Type of study                       Intervention            Number of patients   Time of assessement      (Unless indicated otherwise)
                                                       Jansen et al, 2019      Randomized, multicenter        5% fluorouracil, 5% imiquimod,      624                  12 months             Fluorouracil: 74.7%, imiquimod:
                                                                                                              MAL-PDT, or 0.015% ingenol                                                     53.9%; MAL-PDT: 37.7% and
                                                                                                              mebutate                                                                       ingenol mebutate: 28.9%
                                                       Karrer et al, 2019      Open, interventional,          MAL DL-PDT                          50                   3 months              62%
                                                                               multicenter
                                                       Assikar et al, 2020     Controlled randomized          DL-PDT versus PDT                   26                   3 and 6 months        3 months: DL-PDT: 90.5% and
                                                                               intra-individual                                                                                              PDT: 94.2%; 6 months: DL-PDT:
                                                                                                                                                                                             90.0% and PDT: 94.6%
                                                       Sotiriou et al, 2017    Randomized intra-individual    DL-PDT versus PDT                   23                   12 months             DL-PDT: 78% and PDT: 80.6%
                                                                               comparative
                                                       Lacour et al, 2005      Randomised                     DL-PDT and PDT                      108                  12 weeks              DL-PDT: 74% and PDT: 70%
                                                                               investigator-blinded




Review | Dermatol Pract Concept. 2023;13(4):e2023291
                                                                               controlled phase III
                                                       Genovese et al, 2016    Intraindividual comparative    DL-PDT versus ingenol mebutate      27                   3 months              DL-PDT: 72.4% and ingenol
                                                                                                                                                                                             mebutate: 73.6%
                                                       Wiegell et al, 2012     Randomized multicenter         MAL DL-PDT                          145                  3 months              Grade I AKs: 75.9%, grade
                                                                                                                                                                                             II: 61.2% and grade III: 49.1%
                                                       Ulrich et al, 2021      Vehicle-controlled phase III   BF-200 ALA-PDT versus vehicle       50                   12 months             BF-200 ALA-PDT: 86.0% and
                                                                                                                                                                                             vehicle: 32.9%
                                                       Salido-Vallejo et al,   Single-centre, intraindividual, BF-200 ALA-PDT and DL-PDT          19                   12 weeks              combPDT: 31.6% and
                                                       2020                    retrospective                   (combPDT) versus DL-PDT                                                       DL-PDT: 15.8%
                                                       Gracia-Cazaña et al,    Observational, prospective,    DL-PDT versus DL-PDT plus ingenol   43                   12 months             DL-PDT: 75.2% and DL-PDT plus
                                                       2019                    comparative                    mebutate                                                                       ingenol mebutate: 54.6%
                                                       Petukhova et al,        Randomized, single-blinded,    10- or 20-minute ALA incubation     32                   1 month                20-minute incubation arm:
                                                       2017                    split-face controlled, 2-arm   times, after pretreatment with a                                               microneedle: 76% and sham
                                                                               clinical trial.                microneedle or sham roller                                                     roller: 58%; 10-minute incubation
                                                                                                                                                                                             arm: microneedle: 43% and sham
                                                                                                                                                                                             roller: 38%
                                                       Torezan et al, 2013     Pilot split-face comparative   Microneedling-PDT versus MAL-PDT    10                   1 and 3 months         At day 90, facial erythema (p = .04)
                                                                                                                                                                                             and coarse wrinkles (p = .002)
                                                                                                                                                                                             improved on the microneedling-
                                                                                                                                                                                             PDT side, compared to MAL-PDT
                                                                                                                                                                                             (p = .01).
                                                                                                                                                                                                                Table 1 (continued)




7
8
                                                        +First Author/Year                                                                                                                                           Complete Clearance in %
                                                          of publication                 Type of study                           Intervention                   Number of patients      Time of assessement        (Unless indicated otherwise)
                                                        Torezan et al, 2018      Randomized split-scalp            Calcipotriol-MAL-PDT versus.                20                       3 months                 Calcipotriol-MAL-PDT: 92.1% and
                                                                                 comparative                       MAL-PDT                                                                                       MAL-PDT: 82.0%
                                                        Bullock et al, 2022      Interventional                    Oral vitamin D3 combined with PDT           29 patients in each      3 to 6 months            Oral vitamin D3 combined with
                                                                                 cohort-controlled                 versus MAL-PDT                              group                                             PDT: 72.5% and MAL-PDT: 54.4%
                                                        Maytin et al, 2018       Bilaterally controlled            PDT plus topical 5-fluorouracil             17                       3, 6, 9, and 12 months   PDT plus topical 5-fluorouracil:
                                                                                                                   versus PDT                                                                                    75% and PDT: 45% at 3 months;
                                                                                                                                                                                                                 PDT plus topical 5-fluorouracil:
                                                                                                                                                                                                                 67% and PDT: 39% at 6 months
                                                        Pires et al, 2019        Intra-individual comparative      Acoustic pressure wave ultrasound-          15                       6 months                 Acoustic pressure wave ultrasound-
                                                                                                                   CO2-MAL-PDT versus MAL-PDT                                                                    CO2-MAL-PDT: 72% and MAL-
                                                                                                                                                                                                                 PDT: 65%
                                                        Vrani et al, 2019        Randomized intraindividual        Fractional CO2 laser-PDT versus PDT         42                       12 months                Fractional laser-PDT: 47.2%
                                                                                 comparison                                                                                                                      and PDT: 52.3%
                                                        Togsverd-Bo et al,       Randomized comparative            Fractional CO2 laser-PDT versus PDT         15                       3 months                 Fractional laser-PDT: 88%
                                                        2012                                                                                                                                                     and PDT: 59%
                                                        Bento et al, 2021        Randomized controlled four-       DL-PDT; DL-PDT + microneedles;              40 patients, 10          3 and 6 months           The DL-PDT+ microneedles group
                                                                                 arm comparative                   DL-PDT + CO2 laser; DL-PDT +                patients at each group                            had a higher AK-clearance after 1
                                                                                                                   microdermabrasion                                                                             (p=0,002) and 3 (p=0,034) months.
                                                                                                                                                                                                                 Similar in every group at 6 months
                                                                                                                                                                                                                 (p=0,441)
                                                        Togsverd-Bo et al,       Randomized controlled             Ablative fractional laser (AFL)-assisted    16                       3 months                 AFL-dPDT: 74%, DL-PDT: 46%,
                                                        2015                                                       DL-PDT) (AFL-dPDT) versus DL-                                                                 PDT: 50% and AFL: 5%
                                                                                                                   PDT), PDT and AFL alone (AFL)
                                                        Togsverd-Bo et al,       Randomized intra-individual       Repeated PDT every 6 months for AK          25                       3 years                  New AKs in 63% of patients in
                                                        2015                     controlled                        prevention                                                                                    untreated skin areas versus 28% of
                                                                                                                                                                                                                 patients in PDT-treated skin
                                                        Piacquadio et al,        Randomized, parallel-group,       ALA 2x versus ALA 3x versus                 166                      52 weeks                 ALA 2x: 36.0%, ALA 3x: 37.5%,
                                                        2020                     evaluator-blinded                 vehicle PDT                                                                                   vehicle: 18.9%

                                                       ALA = 5-aminolevulinic acid;BF200-ALA = Nanoscale-lipid vesicle formulation with the prodrug 5-aminolevulinic acid;

                                                       PDT = photodynamic therapy;

                                                       AFXL-PDT = ablative fractional laser resurfacing photodynamic therapy;

                                                       DL = daylight photodynamic therapy;

                                                       MAL-PDT = methyl aminolevulinate photodynamic therapy.




Review | Dermatol Pract Concept. 2023;13(4):e2023291
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Review | Dermatol Pract Concept. 2023;13(4):e2023291                                                                                          11
