Daylight photodynamic therapy in nonmelanoma skin cancers and photorejuvenation

Abstract

Currently, photodynamic therapy (PDT) is widely used, mainly in treatment of actinic keratosis (AK), especially grades I and II following the Olsen classification. The main side effects include burning, stinging, and pain during irradiation. Alternative protocols include daylight PDT (dPDT), which uses sunlight instead of artificial light after applying a photosensitizer. Unlike conventional PDT, daylight therapy is less painful and more comfortable for patients. This article presents the mechanism of dPDT, indications for this method as well as its efficiency, side effects, advantages and disadvantages. In the end, current treatment protocols of dPDT are presented.

Introduction

Photodynamic therapy (PDT) was introduced over three decades ago for the treatment of pre-cancerous stages of nonmelanoma skin cancers, mainly actinic keratosis (AK) [1]. It is widely used due to its non-invasiveness, excellent cosmetic effect, and the possibility of treating broad cancerization field [2]. It works by inducing oxidative stress, which is formed due to the interaction of a photosensitizer, light, and tissue oxygen [3]. Simultaneously, with the destruction of cancer cells, the effect of skin photorejuvenation is observed [4]. The conventional protocol requires artificial blue/red light sources performed in a medical facility [3]. The main side effects are burning, stinging, and pain during irradiation, followed by pain, erythema, erosions, oozing, and swelling during the post-treatment healing period. Sometimes, they might be so disturbing to the patient that treatment discontinuation may be requested [5]. Alternative protocols include daylight PDT (dPDT), which uses sunlight instead of artificial light after applying a photosensitizer. Unlike conventional PDT, daylight therapy is less painful and more comfortable for patients as it requires less frequent visits to a medical facility. However, it is only recommended for mild to moderate actinic keratosis (AK) [6]. This review aims to discuss the multiple applications of dPDT, as well as its advantages and disadvantages.

Mechanism of daylight photodynamic therapy in treating mild to moderate AK and photorejuvenation

The mechanism of PDT is based on photosensitizers, light, and oxygen, which destroy cells and tissues in non-invasive treatment of skin diseases [7]. Some dyes can sensitize cells and cause death of cells after irradiation by light (for example, sunlight in dPDT) [1]. There are two main substances used as photosensitizers: 5-aminolevulinic acid (ALA) or methyl-5-amino-levulinic acid (MAL) [8]. ALA is one of the substrates in the heme biosynthesis pathway. After application on the skin, photosensitization causes an accumulation of protoporphyrin IX (PpIX) [9], which usually accumulates premalignant, malignant, and inflammatory cells rather than normal epidermal cells [10, 11]. The mechanism of PpIX aggregation in the neoplastic cells is supposed to relate to switching the cell’s metabolism from tricarboxylic cycle acid (TCA) to aerobic glycolysis. It is suspected that it may activate the heme biosynthesis pathway to remove TCA metabolites and, as a result, enhance PpIX accumulation [12]. ALA is a pro-drug that converts into the PpIX via the heme biosynthesis pathway [13]. PpIX is mostly sensitized in blue-violet visible light-spectrum (400–430 nm) and slightly less sensitized in red light-spectrum (630–635 nm), but the penetration upon red light is better — about 3 mm into the skin in contrast to blue-violet light-spectrum — about 1mm [14, 15]. The energy from photosensitization results from the irradiation of PpIX production of an excited singlet electronic state by UV/visible photon [16, 17]. After photosensitization, oxygen reacts with the sensitizer in a singlet or triplet state, reducing oxygen to superoxide anion radical (O2 • −) [17]. Baptista et al. [17] described two types of oxidation reactions: after photosensitization of a sensitizer (i.e., PpIX), it could induce reaction type I, which causes generating 1O2 with poorly reactive O2• and HO2• as side-products of type I oxidation reaction [18]. Type II of photosensitized oxidation is based on photosensitizer’s oxidation and singlet oxygen production (1O2). Products of photochemical reactions induced by PDT damage unsaturated lipids, amino acids, and DNA bases [16]. The reaction is also cytotoxic to cells, especially mitochondria, where PpIX is first synthesized. It affects the endoplasmic reticulum as well as lysosomes [19]. Finally, the death of cells caused by the aforementioned process could be executed by apoptosis, autophagy, or necrosis [20–22]. Overall, dPDT aims to induce apoptosis [8].

Indications for use of dPDT

Primarily, dPDT is used to treat AK, which is defined as a pre-cancerous lesion, caused by sun exposure, mainly in the middle-aged and elderly and may progress to invasive squamos cell carcinoma (SCC) [23, 24]. AK can be treated with surgical excision, curettage, cryotherapy, PDT, 5-fluorouracil, imiquimod, the new agent tirbanibulin, and diclofenac [25]. The main aim of treatment is to prevent progression to an invasive tumour. International consensuses emphasize the role of dPDT with the preceding application of MAL or ALA cream in AK treatment as an effective and patient-friendly therapy [26–29]. It was observed that ALA cream has the best response compared to MAL cream or placebo [30]. This method is recommended for I and II grades of AK (Olsen classification), especially for wide lesions with good access to daylight. Moreover, studies show a significant advantage of using dPDT for reducing the number of new AKs, which often recur after applying other treatment modalities. According to the effectiveness in the reduction of new lesions, it is comparable to cryosurgery [31]. dPDT is also really promising in actinic cheilitis (AC), which is a special form of AK located on a lip. The latest studies show that dPDT with MAL or ALA cream can be a proper method of AC therapy [27, 32].

Furthermore, dPDT has a promising role in treating basal cell carcinoma (BCC). However, the effectiveness and potential use of the method for treating BCC are limited by the depth of penetration of the prodrug and light. Therefore, its use is recommended mainly for the treatment of thin (< 2 mm) and low-risk BCC. Moreover, it should be emphasized that the primary method of treating BCC is surgical resection, while other methods serve only as alternative treatments when surgical intervention is not feasible, with the overall clearance rates of dPDT being lower than those achieved with surgery. If dPDT is used, it might be combined with other topicals, such as 5% imiquimod cream, enhancing the total treatment response [33, 34].

Some studies point out dPDT as a treatment option in patients with Xeroderma Pigmentosum (XP), who often develop multiple AKs and other non-melanoma skin cancer. dPDT might be used in this group with acceptable effects [35].

Lately, case reports have also shed new light on the use of dPDT in Bowen’s disease with therapeutic success, but more research is required [36, 37].

Another indication to use dPDT is the photorejuvenation effect and improvement in skin condition. It was reported that PDT causes an increase in metalloproteinase level and activity, a decrease in elastosis, and an increase in the amount of collagen fibers. Therefore, finally, it gradually reduces mottled pigmentation, wrinkles, erythema, and tactile roughness. It is usually an additional effect during AK therapy, but studies indicate that it can also be the main reason for the treatment [4, 31].

Efficiency of dPDT

Conventional ALA and MAL PDT are highly effective and safe therapy for AK [2]. However, this procedure is time-consuming and associated with side effects, mainly pain, which limits the area illuminated in a single session [38, 39]. dPDT is an effective treatment of AK, and is an alternative to conventional PDT. The efficiency of both these methods were compared for the first time in 2008 [40]. The randomized, controlled study demonstrated a similar reduction of AK lesions (79% in MAL dPDT and 71% in conventional PDT with MAL) and less pain experienced by patients in dPDT [40]. Rubel et al. confirmed non-inferiority between daylight and conventional PDT. The study on a group of 100 subjects in Australia showed good efficiency of dPDT not only in sunny and cloudy weather conditions [41]. Fai et al., in their analysis based on an Italian population, revealed that MAL dPDT is characterized by high maintenance of complete remissions [42]. Moreover, a study by Lacour et al. [43] points out that dPDT is highly effective even in difficult treatment areas, which do not respond to treatment, such as scalp lesions, as well as facial lesions [43].

dPDT protocol can be performed by patients outside of a medical facility which may result in higher patient satisfaction. In a prospective observational study of 22 subjects with AK who were adequately trained in daylight PDT with the MAL procedure, a complete response in 65.9% of AK lesions after 12 months was achieved. Treatment efficiency was accompanied by patient satisfaction and good tolerability of self-administered dPDT [44].

Although dPDT has a therapeutic effect in sunny and cloudy weather, temperature appears to be a treatment-limiting factor [26, 45]. The impact of weather conditions on dPDT is discussed in the Advantages and Disadvantages of dPDT.

Side effects of dPDT

It is important to underline that dPDT has significantly fewer side effects than conventional PDT, especially when it comes to pain and erythema [46].

Pain is the main problem during PDT. The sensation is usually burning and depends on the size and location of the lesion [47] as well as the individual pain threshold. Most of the studies show that dPDT is definitely less painful than conventional PDT, probably thanks to the lower dose of light, thereby smaller amounts of PpIX [40, 46, 48]. Some studies point out that using dPDT at home is more painful for patients than the same therapy in hospital’s garden. This difference may come from a delay between the application of MAL cream and sun exposure, which leads to a higher accumulation of PpIX in the lesion and a more intense inflammatory response. Additionally, psychological factors and longer sun exposure, which enhances the production of antigen reactive forms, may contribute to the increased pain levels in the home setting [49].

PDT can be followed by erythema and crusting. However, it is tricky to distinguish the effect of the procedure itself from sunburn. Because of that, there are recommendations to use sunscreen on exposed skin during therapy — and on the targeted lesions. Although UVA and UVB photoprotection make treatment more acceptable for patients alongside erythema reduction, it does not reduce the efficiency of the therapy [46].

Advantages and disadvantages of daylight photodynamic therapy

Daylight photodynamic therapy is more simplified, convenient, and less time-consuming for patients in dermatology units than conventional therapy [43, 46]. During this treatment, the incubation time is much shorter (30 minutes) than PDT [27]. Moreover, patients can administer therapy independently, and the instructions are relatively straightforward [44].

However, there are some limitations to dPDT resulting from exposure to UV radiation, weather conditions, especially temperature, and patient compliance outside the clinic [43]. The amount of light required for protoporphyrin IX activation remains contentious. Studies indicate that the effectiveness of dPDT is independent of light dose [41]. Even in Nordic countries, characterized by low daylight intensity, the light dose was sufficient, except for winter days [46]. Furthermore, temperature may limit the use of this therapy. Very often, the beneficiaries of dPDT are older adults who cannot tolerate being outdoors for 2 hours [46]. In addition, low temperatures may reduce the activation of PpIX, contributing to a weaker therapeutic effect [50].

Treatment protocol of dPDT

PDT treatment protocols may differ slightly and depend on weather conditions in specific geographical locations. However, the main steps of the procedure are similar. Firstly, sunscreen application and skin preparation are performed.

Chemical sunscreen application is recommended to reduce the possibility of sunburn under daylight exposure [51]. In one of the first dPDT randomized, controlled studies from 2008, sunscreen was applied in all exposed skin areas, except the daylight-treated areas. However, it was also suggested that sunscreen be applied to treatment areas due to observed adverse events, such as erythema and sunburn [40]. In subsequent studies, a sunscreen without mineral filters was applied on the entire sun-exposed surface of the skin (treated and other body areas) [31, 41, 49].

The surface of AKs should be prepared by removing scales and crusts. The most common method in clinical practice is using a curette [27, 40, 41, 43]. This procedure aims to enhance photosensitizer penetration. However, Hereford et al., in their study, revealed that dPDT without curettage but with one hour of MAL incubation before daylight exposure is as effective as standard dPDT with curettage before 30 minutes of MAL incubation. There was also no difference in adverse effects. This modification of the dPDT treatment protocol may facilitate the procedure, which is crucial, especially for patients performing home-based treatment [52]. Torezan et al. reported that microneedling-assisted PDT is a safe and effective method with superior cosmetic results compared to curettage-assisted MAL-PDT [53]. Another skin preparation method is pretreatment with calcipotriol or topical 5% 5-fluorouracil (5-FU) [27]. Nissen et al. carried out a randomized intra-individual study demonstrating that 7 days of pretreatment with topical 5% 5-FU twice daily increases PDT efficiency. The overall lesion response was 62.7% for the protocol compared to 5-FU and 51.8% for dPDT alone at the three-month follow-up [54].

According to European Dermatology Forum guidelines on topical photodynamic therapy, the dPDT treatment protocol begins with applying an organic sunscreen, followed approximately 15 min later by lesion preparation [2].

The next step of the dPDT treatment protocol includes the application of MAL cream. This step should be preceded by cleaning and curettage of the skin [2]. Wiegell et al., in their survey, found no difference in response rates between the areas treated with 16% MAL and 8% MAL [49]. In the studies, patients spent thirty minutes indoors before the skin areas were exposed to daylight for two hours in a hospital’s garden or outside at home. After two hours of daylight exposure, subjects came indoors to remove MAL [31, 40, 41, 44]. Following the procedure, skin care and appropriate sun protection were recommended [43].

Recently, authors from Great Britain created a special kit (dPDT@home kit) which makes the use of a photosensitizer at home easier and reduces the number of medical visits. However, patients still need medical stuff supervision [55].

Conclusions

The main indication for dPDT is AK, especially grades I and II following the Olsen classification. dPTD may also be considered in treatment of AC, XP, Bowen’s disease, improving skin condition and photorejuvenation. dPDT should be performed between 9 am and 6 pm from March to September to maintain sufficient light dose to achieve therapeutic effect.

The possibility of using the therapy at home, the low cost, affordability, and the low number of adverse reactions make beneficiaries of this therapy satisfied and willing to choose dPTD as a retreatment. The main adverse effects of this kind of therapy include burning, erythema, and pain. Due to the lower accumulation of PpIX, side effects are less severe than those of conventional PDT while maintaining effectiveness. The effects of daylight photodynamic therapy are satisfactory while making the treatment comfortable for the patient. However, some aspects, such as the precise amount of light necessary to maintain the effectiveness of therapy, still need to be clarified. Therefore, the topic requires further investigations. The comparison between dPTD and traditional PTD is presented in Table 1.

Table 1.

The comparison of photodynamic therapy (PTD) and traditional daylight PDT (dPTD)

	PDT	dPDT
Time of ALA incubation	3 hours	30 minutes
Pain	Painful	Less painful
Weather conditions	Not important	Important (can affect treatment)
Time of exposure to light	Shorter than 30 minutes	2 hours
In/out of office options	Performed in office only	Can be performed by patients outside of office

ALA — 5-aminolevulinic acid