Abstract
Background/Aim: Actinic keratoses (AKs) are precursors of squamous cell carcinomas and early intervention is important. Photodynamic therapy (PDT) is often first-choice treatment for widespread AKs. Classic PDT consists of: Superficial curettage, application of 5-aminolevulinic acid or methyl aminolevulinate, incubation and protoporphyrin IX (PpIX) accumulation under occlusion for 3 hours, followed by illumination with red light-emitting diode light (37 J/cm2). Classic PDT is effective in treating AKs, but side-effects include unpleasant pretreatment, severe pain during illumination, inflammation after treatment, and long waiting time in the clinic. Materials and Methods: This targeted mini review describes efforts to counteract side-effects and simplify the procedure considering the clinic capacity. Changes are only acceptable if treatment effect is maintained. Results: We introduce the following procedure changes: (i) reducing pre-treatment pain, bleeding, and oozing by omitting curettage; (ii) long-term illumination for 2 hours during PpIX formation (already in use as daylight PDT) and shortening of incubation time from 3 hours to 30 minutes to minimize pain and inflammation risk. In addition, options of timing, incubation, and illumination indoors and outdoors are discussed, focusing on advantages and disadvantages for patients and clinics. Conclusion: We report several options to counteract side-effects of classic PDT.
Actinic keratoses (AK) are very common skin lesions provoked by ultraviolet radiation. They are frequently found on the face and scalp of bald persons. As large skin areas are exposed during outdoors work, physical activities, and on sun vacations, AK may appear all over and often in high numbers (1, 2). First, they appear as small, red macules and later become hyperkeratotic. The hyperkeratosis may become several millimeters thick, irritating, and cosmetically unacceptable.
AKs are premalignant lesions that may transform into squamous cell carcinoma. It has been the assumption that thick AKs have a higher risk of transformation than thin AKs. However, recent investigations indicate that thickness is not related to dysplasia severity (3, 4). For this reason, the general agreement is that patients with multiple AKs should be treated to avoid the risk of AK progression to squamous cell carcinoma. In these cases, photodynamic therapy (PDT) has become a treatment of choice as very large areas may be treated in one session. As multiple AKs may be considered a chronic condition it is also important that PDT can be used repeatedly, over several years, to treat the lesions without any indication of carcinogenic effect. On the contrary, PDT seems to delay photocarcinogenesis (5).
Classic PDT was introduced to clinicians about 20 years ago and the method is used worldwide. In the treatment of AKs the precursors 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) are applied to the skin causing protoporphyrin IX (PpIX) to form in epidermal cells, primarily the abnormal cells. The PpIX renders the cells very sensitive to visible light and subsequent illumination destroys the cells. The main problem when treating with classic PDT is the side-effects: severe pain during pretreatment and illumination, and the long-lasting inflammation after treatment sessions (6).
This mini review describes efforts to minimize side-effects by changing the classic PDT treatment procedures. Treatment of symptoms by pharmacological or physical methods are only dealt with when additionally reducing side-effects.
Materials and Methods
In Europe, the classic PDT consists of: Superficial curettage, application of ALA or MAL, occlusion for 3 hours, followed by illumination with red light-emitting diode light (LED) 37 J/cm2, and incubation with ALA/MAL until end of illumination. After illumination residue ALA/MAL is rinsed of with water.
In this targeted mini literature review every step in the procedure is reconsidered in detail with the purpose to changing it to a less harmful intervention. In all cases the investigations were performed on AK of the face and scalp only.
The following changes have been considered:
Can curettage be omitted?
Can occlusion be omitted?
Can the incubation and treatment time be shortened?
Can PpIX be activated during its formation, by long-term illumination?
Can LED illumination be replaced by sunlight or other light sources for long-term illumination?
Can illumination be performed outside the clinic?
Can PDT be combined with topical corticosteroid?
All the investigations have been performed to reduce and remove side-effects such as pain, inflammation, light sensitivity after PDT, bleeding, and oozing, and to make the procedure less time consuming for the clinic.
We only include changes with well-documented effects of reducing or counteracting side-effects. In addition, only studies showing treatment efficacy identical to classical or daylight PDT are represented here.
Results
It has been shown that superficial curettage is associated with pain and stinging when MAL is subsequently applied. Secondly, it provokes oozing and bleeding which is a particular problem when treating patients on anticoagulation medication (7). Superficial curettage is not needed to obtain optimal efficacy on AK of the face and scalp (8).
Occlusion to enhance PpIX formation and avoid absorption of MAL/ALA in clothing was not used when the “daylight” modality was introduced (9), showing that occlusion is not essential for full efficacy of PDT when used on uncovered facial skin. This saves time in the treatment procedure.
In classic PDT, PpIX builds up for 3 hours to a very high concentration which, when illuminated, results in very severe pain. In daylight PDT the patients are continuously illuminated for 2 hours during which PpIX is activated as soon as the PpIX molecule is formed (very low concentration), avoiding most pain (9, 10). When the patients are exposed outdoors for 2 hours sunscreen use is in most cases necessary to avoid sunburn. Sunscreen is applied 15 minutes before MAL/ALA and may be considered a complication.
When introducing daylight PDT, the treatment time was shortened from 3 h to 2.5 h (11). It has been suggested to further shorten the illumination time to just 1 hour as the PpIX concentration indicate this is possible (6), and this has also been tried (12, 13). More work is needed to substantiate this change.
To shorten the treatment is one thing. Another is to shorten the ALA/MAL incubation time with the purpose of reducing both inflammation and further formation of PpIX after end of illumination. This can be obtained by shortening the incubation time to 30 min and remove MAL/ALA before the 2 hours of illumination commence (14). The reduction of inflammation can be enhanced further by use of topical corticosteroids applied to the skin just before and just after end of treatment (15), with no change in cure rate, but complicates the procedure when not performed in the same session as the sunscreen. The light source used in classic PDT is most often red LED but may be exchanged with other lamp types or lasers emitting light corresponding to the absorption spectrum of PpIX (16–18). When LED light is substituted by daylight the illumination may take place outside the clinic and save time and space (19). In all cases exposure is preferably performed during PpIX formation to avoid pain and reduce inflammation (10).
When combined, all the mentioned interventions provide full effect on AK cure rate, without pain and with very little inflammation, and address the issue of bleeding in patients treated with anticoagulants.
Discussion
Changing an existing procedure must have a valid purpose. It may be advantageous for the patient, the clinic, or, in an ideal situation, for both. All patients are interested in minimizing side-effects, other side-effects are of importance only to specific groups of patients.
Omitting curettage is preferable for anticoagulated patients. When curettage is not performed the clinic saves time on the procedure itself and, subsequently, on managing oozing and bleeding. For the patients the pain, oozing and subsequent wounding are avoided (20). Additionally, it may be an advantage that MAL/ALA is not displaced by bleeding/oozing with a theoretical risk of diminished treatment efficacy.
The incubation time can be 30 minutes or 3 hours before residual MAL/ALA is removed (14). This is of no significance to the clinic as it is performed just before start of illumination or just after when the patient is managed anyway. In daylight PDT it may be performed by the patients at home and will not prolong their stay in the clinic. The advantage of short incubation time is reduced inflammation and much less light sensitivity after the end of treatment. This lowers the need for staying indoors for the rest of the day, and for covering the skin to reduce side-effects (14). Use of sunscreen with physical filter after PDT reduces visible light activation of PpIX formed after end of treatment and it may reduce unintended inflammation (21).
It is generally accepted that daylight PDT saves much time for the clinic as patients can be illuminated in their own garden (22). However, to avoid a sunburn during illumination, the patients must have an organic sunscreen applied a quarter of an hour before curettage and MAL/ALA application which is a complication to daylight PDT unless illumination takes place in a greenhouse where the glass absorbs UVB, thus preventing sunburn (17). The sunscreen must absorb as little visible light as possible to retain optimal activation of PpIX (23).
PpIX formation starts about 30 min after application of MAL/ALA to curettaged skin and about 60 min after when applied to intact uncurettaged skin (20), and as no or very little PpIX is formed before these timepoints the patients may either stay indoors or safely expose themselves to daylight as there is almost no PpIX to activate. The patients can use these 30 min or 60 min to return from the clinic to their homes and commence the 2 hours of continuous illumination (19).
Daylight PDT cannot always be performed due to climate, low temperature, and rainy weather (24, 25). Alternatives have been developed using lamps emitting wavelengths that can be absorbed by PpIX (18, 26). To use these lamps for 2 hours of illumination the clinic must have staff, space and equipment and it may make treatment planning difficult, especially when the weather changes and planned daylight exposure becomes impossible. On the other hand, the indoor procedure saves time spent on sun protection.
This clearly shows that shortening of the illumination period to e.g. 1 hour would be beneficial, for the patient as well as the clinic, without compromising the continuous activation of PpIX which is the prerequisite for performing gentle PDT, outdoors or indoors (6).
Many attempts at increasing PpIX formation by adding drugs to the skin before MAL/ALA have been made, or by prolonging the incubation time (27). However, no treatment improvement seems to be achieved by these efforts, only increase in side-effects, and the various attempts are not included in this paper.
Inflammation of the skin may be severe enough to last weeks. To counteract this, the short ALA/MAL incubation time is an advantage as it lowers the PpIX formation. Combining the treatment with topical corticosteroids before and immediately after treatment further reduces inflammation (15). The application of corticosteroids, however, complicates the procedure if not performed alongside the application of sunscreen.
This mini review summarizes effective options for counteracting side-effects in PDT and for simplifying the part played by the clinic in the treatment of AKs. When the described changes take place, treating AKs of the face and scalp with classic PDT is outdated.
Footnotes
Authors’ Contributions
Both Authors agreed with the content of the article. Dr. Wulf conceived the research and wrote the manuscript. Dr. Wulf and Dr. Heerfordt reviewed the literature and manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received May 19, 2022.
- Revision received June 2, 2022.
- Accepted June 30, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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