Actinic keratosis (AK) is the most common precancerous skin tumor. It consists of an intraepithelial keratinocytic dysplasia caused by cumulative exposure to UV light and can lead to in situ or invasive squamous cell carcinoma.1,2 The lifetime risk of AK is 50%,3 and this condition is among the most frequent reasons patients visit a dermatologist, absorbing both time and resources.

The known risk for progression to squamous cell carcinoma and the scarcity of evidence regarding prognosis that could indicate which lesions will progress make it necessary to treat all AKs.4,5 Molecular studies of tissue from the region where AKs emerge have found oncogenic mutations secondary to UV radiation that develop over time to display cell atypia and eventually form AKs or squamous cell carcinoma.6 Such studies have informed our understanding of the concept of field cancerization and suggest that the best treatment approach is one that targets the entire field.

Conventional photodynamic therapy (PDT), used increasingly for over 10 years, has become the treatment of choice for AK and field cancerization7 given response rates of 86% clearance at 4 months, recurrence rates under 20%,8 and excellent cosmetic results. Incubation with a photosensitizing agent increases the production of selective protoporphyrin IX (PpIX) by tumor cells. Exposure to light at the appropriate wavelength and dose in the presence of oxygen induces oxidation and cell death.9 This treatment requires dedicated staff, facilities, irradiation equipment, and time. However, the main problem with this modality is pain, and even though steps are taken to alleviate it, treatment must occasionally be interrupted.

Daylight-mediated PDT, which uses direct and air-reflected sunlight, has emerged in response to the need for a simpler and less painful therapy. A role for using natural light to induce a reaction in photosensitized skin was suggested in 2006,10 but it was in a 2007 publication that Batchelor et al.11 first documented the use of this modality and its effectiveness in considerably reducing the total number of AKs on a patient's scalp.

Later, a randomized controlled trial published by a group led by Wiegell in 2008 compared response rates and adverse effects of PDT with red light versus daylight in 29 patients with AK. They found no significant differences in efficacy between the 2 treatments (P=.13). Erythema and crust formation were also similar, but pain was significantly greater when red light was used (P<.0001). This group later suggested that slower activation of the small amounts of PpIX produced gradually in daylight PDT might be less painful than rapid photooxidation of the large amounts of PpIX produced during conventional incubation.12 A 2009 publication showed that a lower concentration (8%) of the photosensitizing agent (methyl aminolevulinate [MAL]) than the one used in the earlier studies (16%) could also be effective, and they established 8J/cm2 as the minimum effective light dose.13 The group then undertook a multicenter trial that was published in 2011.14 Two durations of daylight exposure (1.5hours and 2.5hours) were found to have statistically similar outcomes (response rates, P=.7; pain intensity, P=.94) and adverse effects. Seventy-two percent of patients in the trial were satisfied with daylight PDT. A trial by another group concluded that although the response to daylight PDT was significantly greater when AK was mild (P<.0001), 86% of type II AKs and 94% of type III AKs nonetheless cleared completely or were reduced to a lower grade.15 Other authors reported similar results in Switzerland,16 Brazil,17 and southern Italy.18

After several years of uncertainty and lack of consensus about daylight PDT, given the scarcity of evidence, new phase III clinical trials were recently published.19,20 The aim of the present systematic review was to study the available evidence for the efficacy and safety of daylight PDT in comparison with conventional PDT for treating AK and field cancerization. We evaluated the consistency and quality of the trials published and meta-analyzed the results to obtain a global estimate of effect.

This systematic review and meta-analysis took into consideration the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA recommendations).21

Our review of the available randomized trials comparing daylight to conventional PDT in patients with AK or field cancerization and our meta-analysis of 2 of the trials support the conclusion that the new daylight PDT modality is not inferior to conventional one. The strictest of the expert-proposed definitions of a clinically important difference is 15%. The global effect estimate of–3.9%, favoring conventional PDT, was within this margin and its 95% CI was −6.54% to −0.84%.

One factor that might contribute to the lower daylight PDT response rates of 89.2%19 and 70%20 (vs 92.8%19 and 74%20 for conventional PDT) is the lack of clinical control over the amount of daylight exposure.32 This theory is supported by a larger difference in effect, in favor of the conventional modality, in the PP analysis in comparison with the ITT analysis since patients interrupted conventional PDT because of pain.

The differences in efficacy and adverse effects between the trial of Wiegell et al.12 and the Australian19 and European20 trials may be attributable to the phase design, the first being a phase II trial and the other 2 being phase III trials. The first trial sought preliminary information to support efficacy, the presence of a dose-response pattern, and safety, whereas the 2 more recent trials compared the efficacy of the new modality to one that was already available.

Furthermore, some of the limitations authors initially hypothesized for daylight PDT have been attenuated since it has proven effective in almost any type of weather except rain, for the sake of patient comfort, and cold (below 10°C), to guarantee proper generation of PpIX.29 Likewise, adverse effects, which are all superficial and mild, do not differ greatly between daylight and conventional PDT. Subjective reports of pain on a scale of 0 to 10, however, were significantly lower with daylight PDT in all 3 of the trials we reviewed.12,19,20 Thus, patients tolerate daylight PDT better, prefer this modality, and express greater satisfaction with it.

AK is a prevalent and recurring problem that may progress to squamous cell carcinoma. Therefore, treatments that act quickly and whose effect is maintained are sought.19 Given that daylight PDT is noninferior with regard to efficacy but is better tolerated than conventional PDT, the new modality has been said to offer “gain without pain.”16 One recent study found that 70% of clinicians agreed that the duration of therapy and local reactions diminished adherence to treatment.43 Daylight PDT addresses the problem of risk of malignancy in AK by offering a more cost-effective alternative37 with savings in time, staff, material, and infrastructure. Nevertheless, vigilance after approval of daylight PDT to treat AK is important. The results obtained in controlled clinical trials in which patients have received extensive explanations and even been supervised during daylight exposure may differ from those achieved in routine clinical practice, where patients are often of advanced age.

It is true that response rates are lower in higher grade AK (grade I, 75.9%; grade II, 61.2%; and grade III, 49.1%).15 However, it is also true that all thick AKs become thinner after a single daylight PDT session.15 According to expert opinion, grade III AKs that might be present in field cancerization can be treated, even though it is assumed that their response will be less marked and that more sessions or adjuvant treatments may be needed.29

Thus, daylight PDT can be considered a first-line therapy for immunocompetent patients with grade I or II AK or field cancerization on the face or scalp according to the consensus statement of European Society for Photodynamic Therapy in Dermatology.29

Use of this modality in transplanted patients or other immunocompromised individuals can be taken under advisement, but further study will be needed in this population, which is particularly susceptible to the development of AK and nonmelanoma skin cancer. We also lack evidence of the efficacy of daylight PDT on other skin lesions, although anecdotal reports of its application in basal cell carcinoma,44 Bowen disease,45 and actinic cheilitis46 have been published.

The trials we selected have certain design flaws, such as the lack of specification of the randomization and blinding methods in the Danish study,12 and the short duration of follow-up (3 months) in both that study and the European multicenter one.20 However, the Australian study found that outcomes were satisfactory at 6 months.19 Bias that might result from lack of patient blinding when pain is reported has already been mentioned, but complete patient blinding in PDT is practically impossible. Therefore, the trials included in the meta-analysis can be considered to have been very well designed, lending support to their internal validity and, in consequence, to the global estimate of efficacy. The fact that only 2 trials could be included in the meta-analysis, however, makes it difficult to draw conclusions and reveals the need to continue to study daylight PDT.

A difficulty we encountered was the lack of sufficient information on the intensity of reported pain and lack of access to data. Such information would have been useful for calculating a global effect estimate of this adverse effect. The differences found, however, show a high level of clinical significance in the analyzed trials,19,20 where pain ranged from “sometimes unbearable” to “practically painless” and the Wilcoxon test found daylight PDT to be significantly superior (P<.001) in this respect.

To avoid publication bias, we searched for both published and unpublished trials on known databases, reviewed reference lists, and contacted experts in the management of daylight PDT. The trials we found, therefore, seem to represent the scope of research on this topic.

The external validity and applicability of the results are supported to a certain extent by the fact that the 2 meta-analyzed trials were carried out in geographic areas with different climates.

Daylight PDT is not inferior to conventional PDT in the treatment of mild to moderate AK and field cancerization. The efficacy of this modality does not depend on weather conditions and has been applied at different latitudes. The procedure is practically painless, is better tolerated than conventional PDT, and does not have important adverse effects. Cosmetic outcomes are very good and patient satisfaction is high. Daylight PDT's profile of efficacy, tolerability and safety will probably make this modality a treatment of choice for AK and field cancerization.

The authors declare that they have no conflicts of interest.