Photodynamic therapy (PDT) has become established as a treatment for actinic keratosis (AK), Bowen disease, and certain types of basal cell carcinoma over the past decade because it is highly effective for these dermatoses and gives excellent cosmetic results.1–5 PDT is currently included in clinical guidelines for treating nonmelanoma skin cancers1,4,6–10 and is considered the first line of therapy for multiple AKs and field cancerization.4,11–15 The range of indications for PDT has broadened in recent years and now encompasses infectious conditions,16–19 inflammatory dermatoses,8,20–22 adnexal diseases,23–25 skin tumors,17,26–28 and photoaging.8,29–31 The potential value of PDT as a preventive treatment in transplant patients or those with conditions that are difficult to manage, such as Gorlin syndrome, has also been recognized.32–36 However, the application of conventional PDT10 is a laborious, time-consuming process for health professionals and patients alike and requires special equipment that takes up space in a clinic. The classic protocol10 specifies that the photosensitizer should be applied and kept covered (occlusion) for a certain period—usually 4to 6hours or more for 5-aminolevulinic acid (5-ALA) or 3 hours for the 5-ALA methylester, or methyl aminolevulinate (MAL). After incubation, the area is exposed to an appropriate source of light. The most common combinations of light sources and doses used in Europe are the Aktilite (Galderma, Lausanne, Switzerland) at 37J/cm2 for approximately 8minutes and the Waldmann PDT 1200L (Waldmann GmbH & Co, Villingen-Schwenningen, Germany) at 75to 100J/cm2 for approximately 20minutes. PDT is not free of adverse effects.37–44 The most common one, and the most limiting, is pain during illumination, which must sometimes be interrupted; analgesia or local or regional anesthesia may be required.45,46

With the use of portable light sources (Fig. 1) to optimize the procedure and facilitate outpatient treatment,47–49 the concept of ambulatory PDT has emerged.50 This modality is costly, however, and is only useful for treating small lesions. The most important methodological simplification introduced in recent years has been the therapeutic use of daylight.51,52

Figure 1.

Ambulatory photodynamic therapy using portable light sources.50 A, Ambulight (Ambicare Health Ltd, St Andrews, Fife, UK) (http://www.ambicarehealth.com/ambulight-pdt/). This device uses an adhesive patch with a red light emitting diode (LED)—peak emission 640±25 nm—that delivers a dose of 75J/cm2. Light intensity is low (7mW/cm2) and exposure lasts for 3h.49 Image used with the permission of Ambicare Health Ltd. B, AK-derm (Sellas GmbH, Ennepetal, Germany). High-intensity LED (70–80mW/cm2) that emits 37J/cm2 in 8min; peak emission is 630nm±5nm. Image used with permission of Dr Helger Stege (Klinikum Lippe, Detmold, Germany).

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Daylight PDT uses a combination of direct and reflected sunlight outdoors.53 Using the sun as a light source has encouraged more widespread use of PDT, has lowered costs considerably, and has enhanced adherence.

Key Questions and ConcernsWhat Patients Are Candidates for Daylight-Mediated PDT?

This modality is mainly appropriate for cooperative patients who have multiple AKs (preferably grade I or II) or field cancerization in sun-exposed areas and who find conventional PDT to be very painful. Daylight PDT will probably gradually come to be used for skin diseases other than AK.

What Light Dose Is Needed for Effective Activation of PpIX?

The amount of irradiation received in 2hours of direct sunlight at midday varies greatly according to geographic location, weather conditions, and season.60 The threshold dose for PpIX activation (at which daylight PDT will be effective for destroying AKs) varies in studies published to date (8, 6, and 3.5J/cm2).53,57,58,60 Until the effective dose is established more precisely, a threshold of 8J/cm2 is currently considered adequate to ensure that therapy will be effective.60 Using meteorological models and dosimeters installed at a number of geographic locations it has been possible to establish the effective light doses for activating PpIX in 2hours of exposure at midday on the fifteenth day of each month at different latitudes.53 Accordingly, it would be possible to reach daylight doses over 8J/cm2 in Spain in any month, depending on weather conditions; this treatment could therefore be completed within the 2-hour time frame all year round53 (Table 3).

Table 3.

Light Dose Received in 2h of Exposure at Midday in the Middle of Each Month at the Range of Latitudes in Which Spain Is Included. a

Latitudes	Effective Light Dose in 2h of Exposure on a Sunny Day, J/cm2
	Months
	1	2	3	4	5	6	7	8	9	10	11	12
50N	13	21	31	40	46	48	47	43	35	25	16	11
40N	23	31	40	47	51	52	51	48	42	34	25	21
30N	33	39	47	52	54	54	54	52	48	42	34	31

a

Spain extends from about the 30°N (Punta de Tarifa) to 43°47¿N (Estaca de Bares). Columns show months by number. Months are expressed as numbers; 1 indicates January, 2 indicates February, etc. Adapted from Wiegell et al.53

How Should the Lesions Be Exposed to Daylight?

Exposure should take place outside in the middle of the day and last 2hours.57 However, Grinblat and colleagues (unpublished, Euro-PDT meeting) used shorter exposure times of 60to 90minutes and observed results that were similar to those of multicenter studies.57,58 Considering at the PpIX activation range corresponds to visible light, which passes through glass, Hospital Molhom in Vejle, Denmark, uses a glass structure to protect patients from certain weather conditions and increase comfort during exposure (Fig. 2).

Figure 2.

Greenhouse where the patient is exposed to daylight for photodynamic therapy at Hospital Molhom in Vejle, Denmark. Photograph kindly provided by Dr Peter Bjerring.

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What Period of the Year Is Most Appropriate for Daylight-Mediated PDT?

It seems to be possible to provide treatment at midday all year round in Spain unless there is a thick cloud cover.53 Temperature may be a limiting factor, however, as studies in vitro and in mice suggest that low temperatures reduce PpIX production.60–62 Low temperatures also make it difficult for the patient to stay outside during exposure. A temperature range of 10°C to 35°C for daylight PDT has been recommended,60 but there is room for variation according to patient characteristics and exposure location. To date, no studies have demonstrated that there are differences in treatment efficacy outside this temperature range.

Wiegel and colleagues60 a linear association between the UV index and the light dose that activates PpIX production during exposure at midday (11am to 1pm) for 2hours; when the UV index exceeds 3, patients receive over 8J/cm2 in this period. Weather conditions also play a part, as the effective daylight dose can decrease 25% on partly cloudy days, 50% on cloudy days, and 75% on rainy days.53,60 The exposure time required on such days has not been determined, and although some authors recommend not scheduling this modality of PDT on rainy57 or very overcast63 days, it would be useful to more precisely determine the required conditions for delivering the minimum effective light dose.

Why Is a Sunscreen Needed and What Sunscreen Is Appropriate for PDT?

The recommendation to use a sunscreen aims mainly to prevent the adverse effects of UV radiation during exposure to sunlight. Sunscreens used to date have varied in their SPF levels, ranging from SPF 15,59 to SPF 20,53,57 to SPF 30 and SPF 50 (by Grinblat and colleagues and by Le Pillouer-Prost, respectively; unpublished reports, Euro-PDT meeting). Similar outcomes have been observed with all of these sunscreens. It is important to use one that does not contain mineral filters, which might block the visible light necessary for PpIX activation in addition to UV radiation. A list of sunscreens appropriate for use in daylight-mediated PDT has been provided by the Spanish company Laboratorios Galderma SA. It includes the following products: from Laboratorios Uriage, Bariesun cream, SPF 30/50; from Laboratorios Ducray, Melascreen solar emulsion, SPF 50; from Laboratorios Eucerin, Sun Spray transparent, SPF 30/50; from Laboratorios Bioderma, AKN Mat SPF 30/UV-A 13, MAX cream, SPF 50+/UV-A 38 and AKN Spray SPF 30/UV-A13; and from Laboratorios ISDIN, a transparent SPF 30 gel-cream.

What Limitations Affect Daylight-Mediated PDT?

Daylight-mediated PDT is of great benefit for certain patients and for dermatologists who have neither the time nor the infrastructure for conventional PDT. However, there are certain limitations, such as the difficulty of scheduling sessions because of unpredictable weather and the constraints imposed by climate conditions in some geographic areas. At northern European latitudes, solar radiation is insufficient and temperatures are too low to accommodate sessions during some seasons (autumn and winter). Conditions in countries like Spain are different. It is still unclear whether very intense exposure for 2hours at our latitudes might be risky for our patients, but the Australian clinical trial described above has shown that daylight-mediated PDT is effective and safe in countries with strong solar radiation. Another problematic issue is the lack of rigorous control over therapy during the ambulatory outdoor period of the procedure, as the patient is the one who monitors illumination. To date, we still do not know the impact these possible differences might have on the effectiveness of therapy. In addition, daylight PDT seems to be less effective than conventional PDT for grade III AKs, and for the moment we lack sufficient evidence to support daylight-mediated PDT for other types of skin lesions. We expect to have new data in the future, however.

The dermatology services under the Integrated Management System in Vigo (at Complejo Hospitalario Universitario de Vigo [CHUVI] and Hospital San Jorge in Huesca [HSJ]) have used daylight-mediated PDT in 35 (CHUVI) and 9 (HSJ) patients with multiple grade I, II or III AKs, or field cancerization. Lesions were located on the face and/or scalp (CHUVI and HSJ) or legs (HSJ). Most patients were treated in a single session, but some underwent 2 sessions (HSJ). The results (Fig. 3) were similar to those achieved with conventional PDT for grade I or II AKs but inferior for grade III AKs. The main adverse effects were inflammation and crusting in the treated area. These effects were less intense, however, than those usually seen after conventional PDT (Fig. 4). Patients treated in the CHUVI reported less pain (scores, 0–3 on a scale of 0 to 10) after daylight mediated PDT than after conventional PDT (scores, 6–10) Most patients who had previously undergone conventional PDT expressed a clear preference for the daylight-mediated modality. The use of this approach allowed us to schedule treatment more quickly and accommodate all of them. Daylight was particularly useful for treating CHUVI patients who lived outside the city, and this choice also considerably reduced the amount of time the CHUVI staff spent preparing and supervising therapy.

Figure 3.

Results of treating multiple AKs with daylight photodynamic therapy (PDT). Photographs in the left column show lesions before treatment. Photographs on the right show the same lesions after treatment. Follow-up images in cases 1to 3 (Complejo Hospitalario Universitario de Vigo, of the Integrated Management System in Vigo) were taken 3mo after a single PDT session. Follow-up images in cases 4and 5 (Hospital San Jorge, Huesca) were taken 8mo after 1 PDT session and 4mo after 2 PDT sessions, respectively.

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Figure 4.

A, Baseline appearance of treated actinic keratosis lesions. B, Erythema and inflammation 3h after treatment. The lesions in the upper photographs (1A and B) were treated with daylight photodynamic therapy (PDT). The lesions in the lower photographs (2A and B) were treated with conventional PDT. Photographs from Hospital San Jorge.

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Daylight-mediated PDT is an important new modality in dermatology. It has proven to be as effective as conventional PDT for treating AK and is a technically simpler method. Tolerance of therapy has improved considerably with the use of natural light. Both patients and specialists often express a preference for daylight PDT because the ambulatory procedure is simple and easy to organize. However, important disadvantages are that it is difficult to schedule because of weather conditions at certain times of the year and because light exposure is difficult to control. Over time, this modality will probably begin to have applications in the treatment of skin conditions other than AK, as has occurred with conventional PDT in recent years.

Although a protocol for daylight-mediated PDT has been proposed57 and an international consensus paper has been published,53 many aspects remain speculative to a certain degree and need to be defined in the short-term so treatment can be fully standardized. Some of these aspects are the obligatory use of a sunscreen, the most appropriate SPF for this clinical use, the ideal amount and concentration of photosensitizer, whether occlusion is necessary, the effective daylight dose required for PpIX activation, the exact exposure time required at different times of day and in specific weather conditions, the real effect of ambient temperature on efficacy, and the possible use of photosensitizers other than MAL.

According to information available at this time, Spain has an ideal climate for providing daylight PDT all year round. Existing international treatment protocols are currently based on conditions in Nordic countries. In order to adapt them to other settings, a clinical trial is currently under way in several European countries, including Spain, and the results are expected to be available soon. The findings will help us establish optimal procedures for applying daylight PDT in Spain.

Dr Lidia Pérez has attended Spanish and international meetings about PDT at the invitation of Laboratorios Galderma SA; she was a speaker at the first meeting organized by that company on PDT in Galicia. Dr Yolanda Gilaberte has received consulting fees from Laboratorios Galderma SA; she has received fees for speaking for that company at various conferences.