Switching From Conventional Photodynamic Therapy to Daylight Photodynamic Therapy For Actinic Keratoses: Systematic Review and Meta-analysis

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Tomás-Velázquez, P. Redondo" "autores" => array:2 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Tomás-Velázquez" ] 1 => array:2 [ "nombre" => "P." 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A, Receding hairline in the frontotemporal region, extending to the retroauricular region. B, The skin in the region of alopecia shows surface scarring, with loss of follicular orifices, uniform paleness, and a vascular network. C, Trichoscopy image at the frontal hairline, in which absence of follicular ostia, erythema, perifollicular scaling, and branched capillaries can be observed. D, Trichoscopy image of the retroauricular region in which similar changes to those described above can be observed." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Esteban-Lucía, A.M. Molina-Ruiz, L. Requena" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Esteban-Lucía" ] 1 => array:2 [ "nombre" => "A.M." "apellidos" => "Molina-Ruiz" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Requena" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731016304410" "doi" => "10.1016/j.ad.2016.11.012" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731016304410?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219017300598?idApp=UINPBA000044" "url" => "/15782190/0000010800000004/v1_201704280927/S1578219017300598/v1_201704280927/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Switching From Conventional Photodynamic Therapy to Daylight Photodynamic Therapy For Actinic Keratoses: Systematic Review and Meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "282" "paginaFinal" => "292" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Tomás-Velázquez, P. Redondo" "autores" => array:2 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Tomás-Velázquez" "email" => array:1 [ 0 => "atomas.1@alumni.unav.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Redondo" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Dermatología, Clínica Universidad de Navarra, Pamplona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "De la terapia fotodinámica convencional a la terapia fotodinámica con luz de día en el tratamiento de las queratosis actínicas: revisión sistemática y metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1113 "Ancho" => 2379 "Tamanyo" => 114426 ] ] "descripcion" => array:1 [ "en" => "Forest plot comparing response rates for conventional versus daylight PDT according to intention-to-treat analysis. The figure shows that the CIs were below the noninferiority margins established a priori (20% by Rubel et al.19<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 15% by Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>). Thus, daylight PDT can be considered noninferior. PDT refers to photodynamic therapy and diff. to difference." ] ] ] "textoCompleto" => "IntroductionActinic 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.<a class="elsevierStyleCrossRefs" href="#bib0235">1,2</a> The lifetime risk of AK is 50%,<a class="elsevierStyleCrossRef" href="#bib0245">3</a> 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.<a class="elsevierStyleCrossRefs" href="#bib0250">4,5</a> 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.<a class="elsevierStyleCrossRef" href="#bib0260">6</a> 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 cancerization<a class="elsevierStyleCrossRef" href="#bib0265">7</a> given response rates of 86% clearance at 4 months, recurrence rates under 20%,<a class="elsevierStyleCrossRef" href="#bib0270">8</a> 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.<a class="elsevierStyleCrossRef" href="#bib0275">9</a> 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,<a class="elsevierStyleCrossRef" href="#bib0280">10</a> but it was in a 2007 publication that Batchelor et al.<a class="elsevierStyleCrossRef" href="#bib0285">11</a> 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.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> 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.<a class="elsevierStyleCrossRef" href="#bib0295">13</a> The group then undertook a multicenter trial that was published in 2011.<a class="elsevierStyleCrossRef" href="#bib0300">14</a> 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.<a class="elsevierStyleCrossRef" href="#bib0305">15</a> Other authors reported similar results in Switzerland,<a class="elsevierStyleCrossRef" href="#bib0310">16</a> Brazil,<a class="elsevierStyleCrossRef" href="#bib0315">17</a> and southern Italy.<a class="elsevierStyleCrossRef" href="#bib0320">18</a>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.<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> 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.MethodsThis systematic review and meta-analysis took into consideration the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA recommendations).<a class="elsevierStyleCrossRef" href="#bib0335">21</a>Sources and Search StrategyOur sources of articles were MEDLINE, the Cochrane Central Register of Controlled Trials, the Web of Science, and the registry of clinical trials of the US National Institutes of Health.The first search was done in June 2015. The same search strategy was repeated in December 2015. We used the following search terms: actinic keratoses and daylight photodynamic therapy. In the PubMed portal we added the term randomized or randomised. No year or language restrictions were introduced, and we read articles in both English and Spanish. Full texts were accessed. In addition, we consulted experts and contacted one of the authors of the included studies to be sure we had not missed any important trials and to check that we had understood certain trial characteristics and analyzed them correctly. We also consulted the gray literature to avoid publication bias. The reference lists of all studies found were also reviewed.Inclusion CriteriaInclusion was restricted to randomized controlled trials that evaluated the efficacy or noninferiority of daylight PDT versus conventional PDT in humans with AK. This decision was based on the need to determine that daylight PDT is no less effective than conventional PDT and that it was better tolerated by the patient, being simpler and more cost-effective.Any population, age group, or body area exposed could be included. Duration of follow-up was not a selection criterion, and no restrictions were placed on the PDT protocol followed.Article Selection Process, Data Items and Extraction, and Analysis of Quality of Trial DesignWe first completed the search, evaluated the studies, and synthesized their results.The 2 main variables established a priori were lesion response rate and pain caused by the procedure. Other variables, such as AK grade, other adverse effects, patient satisfaction, cosmetic results, duration of follow-up, statistical approach, or blinding were also taken into account.The search was unblinded with regard to authors, journals, and research facility.We consulted the Jadad scoring system for randomized trials,<a class="elsevierStyleCrossRef" href="#bib0340">22</a> and our critical analysis was based on the CONSORT reporting guidelines.<a class="elsevierStyleCrossRef" href="#bib0345">23</a>Statistical AnalysisThe meta-analyzed variable was the percentage of lesions with a complete response (number of fully cleared lesions as a percentage of the number treated) at week 12. We calculated the difference between the mean rate of response to daylight PDT and the mean rate of response to conventional PDT; we also calculated 95% CIs. A fixed-effects meta-analysis was performed according to the inverse variance method. Both per-protocol (PP) and intention-to-treat (ITT) analyses were carried out. Noninferiority of efficacy of daylight versus conventional PDT was demonstrated based on the expert-established thresholds for a clinically significant difference in effect between treatments: 20% according to Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 15% according to Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>ResultsTrial SelectionTwenty articles were identified in the MEDLINE search, 14 in the Cochrane database, and 11 in the Web of Science. Two more gray literature articles were found, for a total of 47 articles in all. Twenty repeated titles were discarded. Of the 27 remaining, 21 were discarded because they clearly failed to meet the inclusion criteria. Four compared aspects of PDT that were not of interest<a class="elsevierStyleCrossRefs" href="#bib0350">24–27</a> (photosensitizing agents vs placebo, effectiveness of different photosensitizing agents, artificial daylight vs red light-emitting diodes [LED] vs daylight vs white LED), 9 were not randomized trials (3 expert consensus reports or international association opinions,<a class="elsevierStyleCrossRefs" href="#bib0370">28–30</a> 3 qualitative reviews,<a class="elsevierStyleCrossRefs" href="#bib0315">17,31,32</a> 1 retrospective case series,<a class="elsevierStyleCrossRef" href="#bib0310">16</a> 1 letter to the editor,<a class="elsevierStyleCrossRef" href="#bib0395">33</a> and 1 conference summary<a class="elsevierStyleCrossRef" href="#bib0400">34</a>). The remaining 8 articles also discussed issues different from the objective of our study (the use of different photosensitizing agents,<a class="elsevierStyleCrossRef" href="#bib0405">35</a> photosensitizer concentration required for effective daylight PDT,<a class="elsevierStyleCrossRef" href="#bib0410">36</a> cost-effectiveness of daylight PDT versus LED PDT,<a class="elsevierStyleCrossRef" href="#bib0415">37</a> fractional ablative laser treatment in combination with daylight PDT,<a class="elsevierStyleCrossRef" href="#bib0420">38</a> effect of applying a sun screen to reduce inflammation after daylight PDT,<a class="elsevierStyleCrossRef" href="#bib0425">39</a> effect of weather on daylight PDT in Australia,<a class="elsevierStyleCrossRef" href="#bib0430">40</a> PDT results in transplanted patients,<a class="elsevierStyleCrossRef" href="#bib0435">41</a> and PDT for head and neck tumors<a class="elsevierStyleCrossRef" href="#bib0440">42</a>). Following in-depth study of the 6 remaining articles, 3 more were excluded because they did not have the aims required for inclusion.<a class="elsevierStyleCrossRefs" href="#bib0295">13–15</a>Finally, 3 randomized trials comparing daylight PDT to conventional PDT were included in this systematic review.<a class="elsevierStyleCrossRefs" href="#bib0290">12,19,20</a> One of them<a class="elsevierStyleCrossRef" href="#bib0290">12</a> was excluded from the meta-analysis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Trial and Participant CharacteristicsThe characteristics of all 3 trials qualitatively reviewed are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>These 3 all treated 2 symmetrical areas in the same patients (intraindividual comparison) and used MAL as the photosensitizing agent. After application of MAL, daylight exposure of 1 of the areas started before 30minutes had elapsed; exposure continued for 2to 2.5hours. On the comparator area, the photosensitizer was left incubating for 3hours, after which the skin was exposed to red light.Trial QualityThe results of our analysis of quality based on the CONSORT reporting guidelines for randomized clinical trials<a class="elsevierStyleCrossRef" href="#bib0345">23</a> were as follows.The method used to measure adverse effects could have been made more explicit in the study by Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> These authors could also have explained their inclusion criteria more specifically and added a table showing patients’ baseline characteristics. In addition, they did not specify how the randomization sequence was generated, how researchers were blinded, or whether the dermatologist who assessed the response was blinded. CIs were not calculated and limitations were not listed.The other 2 trials, published in 2014 and 2015, shared the same design features. They were randomized investigator-blinded controlled trials lasting 24 weeks (Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a>) and 12 weeks (Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>). They both compared intraindividual efficacy (noninferiority) and safety (superiority in terms of less pain) of daylight PDT versus conventional PDT for facial/scalp AK. Their aims, the design, and criteria were clear and specific. Tables describing the sample and interventions were provided, and the authors explained how variables were assessed. Statistical power was reported and the randomization and blinding procedures were explained. They included both PP and ITT analyses, calculated 95% CIs, described adverse effects, and listed limitations (simple blinding,<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> the difficulty of generalizing findings because of climate differences,<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and the follow-up time<a class="elsevierStyleCrossRef" href="#bib0330">20</a>). Both complied with ethical standards.Only the researchers were blinded in all 3 trials. Pain is a subjective, patient-reported variable and a patient's answers might change if the aim of the study and treatment assignment is acknowledged, possibly biasing the information that can be obtained.The information in each of the studies is summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>All 3 trials were registered at clinicaltrials.gov.Trial Results<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the findings of each of the 3 trials reviewed.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>EfficacyWiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> found that the 2 modalities had statistically similar levels of efficacy (P=.13) and saw that response to daylight PDT did not vary with light intensity.Rubel et al.,<a class="elsevierStyleCrossRef" href="#bib0325">19</a> who established 20% as the margin of difference to demonstrate noninferiority, found that the rate of complete response to daylight PDT (89.2%) was not statistically inferior to the response to conventional PDT (92.8%) at 12 weeks (difference,–3.6%; 95% CI, −6.8% to −0.3%). Moreover, clearance was maintained by 96% of the mild lesions at 24 weeks. The findings of Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> were consistent with the other 2 trials. Using a noninferiority margin of 15%, they observed complete response rates of 70% for daylight PDT and 74% for conventional PDT (difference,–4%; 95% CI, −9.5% to 2.4%). They also concluded that daylight PDT was effective in different weather conditions (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Thus, daylight PDT is effective and not inferior to conventional PDT.Patient-Reported PainPain was significantly greater in the area treated with conventional PDT (P<.0001) in the trial of Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a>; although that result was unrelated to the level of PpIX fluorescence (P=.065), it was related to the effective light dose received (P=.041). Patients in the Australian<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and European<a class="elsevierStyleCrossRef" href="#bib0330">20</a> trials found daylight PDT to be nearly painless and certainly less painful than conventional PDT (P<.001).Adverse EffectsWiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> reported that erythema and crusts formed after both the daylight and conventional PDT treatments to a statistically similar degree and that the effects did not differ between treatment areas in 38% of the patients.Adverse effects in the phase III trials<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> were all dermatologic and mild. The most common effect was a skin rash, and in one of the trials 79% of patients treated with daylight PDT were not inconvenienced by any adverse effect.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>Thus, daylight PDT does not have adverse effects that cause discomfort to patients.Patient SatisfactionSixty-two percent of the patients treated by Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> preferred daylight PDT. Satisfaction with this modality was also greater (P<.001) in the Australian trial.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> In the European trial, 64.8% of the patients were highly satisfied with daylight PDT (vs 18.9% with conventional PDT).Cosmetic ResultsCosmetic results after both treatment modalities were rated good or excellent by 90% to 99.7% of the patients in the 2 phase III trials.<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a>Meta-analysisWe meta-analyzed the results of only the 2 phase III trials.<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> The earliest trial reviewed<a class="elsevierStyleCrossRef" href="#bib0290">12</a> was excluded from the meta-analysis because it used a phase II design whose objective was mainly photobiologic, to open doors to the use of this modality by demonstrating the continuous and effective production of PpIX in daylight.The 2 later trials included a total of 186 patients in the PP analysis and 208 in the ITT analysis.<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> A total of 4668 AKs were treated, 2336 with daylight PDT and 2332 with conventional PDT.The difference between response rates (PP analysis) was 3.6% in the Australian trial<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 4% in the European<a class="elsevierStyleCrossRef" href="#bib0330">20</a> one. The global estimate of the mean response rate difference was −3.69% in favor of conventional PDT. Because the estimate of effect size in the Australian trial was closer to the estimated effect derived from meta-analysis, greater weight was assigned to this trial (77.02% vs 22.98% to the European trial). The I2 test result was 0.0%, as heterogeneity was very low between the 2 trials, whose design and results were similar (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Therefore, we did not perform further measures of heterogeneity. The results of the ITT analysis were similar, yielding a global effect estimate of 3.4% in favor of conventional PDT (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Thus, although conventional PDT is associated with higher response rates than daylight PDT, the difference is not clinically important, as it is less than the difference margins (20% and 15%) established a priori. The 95% CIs of the global effect estimates ranged from −6.54% to −0.84% and −6.10% to −0.70% in the PP and ITT analyses, respectively. Therefore, daylight PDT can be considered noninferior to conventional PDT.DiscussionOur 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%<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 70%<a class="elsevierStyleCrossRef" href="#bib0330">20</a> (vs 92.8%<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 74%<a class="elsevierStyleCrossRef" href="#bib0330">20</a> for conventional PDT) is the lack of clinical control over the amount of daylight exposure.<a class="elsevierStyleCrossRef" href="#bib0390">32</a> 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.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> and the Australian<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and European<a class="elsevierStyleCrossRef" href="#bib0330">20</a> 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.<a class="elsevierStyleCrossRef" href="#bib0375">29</a> 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.<a class="elsevierStyleCrossRefs" href="#bib0290">12,19,20</a> 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.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> 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.”<a class="elsevierStyleCrossRef" href="#bib0310">16</a> One recent study found that 70% of clinicians agreed that the duration of therapy and local reactions diminished adherence to treatment.<a class="elsevierStyleCrossRef" href="#bib0445">43</a> Daylight PDT addresses the problem of risk of malignancy in AK by offering a more cost-effective alternative<a class="elsevierStyleCrossRef" href="#bib0415">37</a> 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%).<a class="elsevierStyleCrossRef" href="#bib0305">15</a> However, it is also true that all thick AKs become thinner after a single daylight PDT session.<a class="elsevierStyleCrossRef" href="#bib0305">15</a> 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.<a class="elsevierStyleCrossRef" href="#bib0375">29</a>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.<a class="elsevierStyleCrossRef" href="#bib0375">29</a>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,<a class="elsevierStyleCrossRef" href="#bib0450">44</a> Bowen disease,<a class="elsevierStyleCrossRef" href="#bib0455">45</a> and actinic cheilitis<a class="elsevierStyleCrossRef" href="#bib0460">46</a> 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,<a class="elsevierStyleCrossRef" href="#bib0290">12</a> and the short duration of follow-up (3 months) in both that study and the European multicenter one.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> However, the Australian study found that outcomes were satisfactory at 6 months.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> 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,<a class="elsevierStyleCrossRefs" href="#bib0325">19,20</a> 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.ConclusionDaylight 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.Ethical DisclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this investigation.Confidentiality of dataThe authors declare that no private patient data are disclosed in this article.Right to privacy and informed consentThe authors declare that no private patient data are disclosed in this article.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres834127" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec830164" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres834126" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec830163" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Sources and Search Strategy" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion Criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Article Selection Process, Data Items and Extraction, and Analysis of Quality of Trial Design" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical Analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Trial Selection" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Trial and Participant Characteristics" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Trial Quality" ] 3 => array:3 [ "identificador" => "sec0055" "titulo" => "Trial Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Efficacy" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Patient-Reported Pain" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Adverse Effects" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Patient Satisfaction" ] 4 => array:2 [ "identificador" => "sec0080" "titulo" => "Cosmetic Results" ] ] ] 4 => array:2 [ "identificador" => "sec0085" "titulo" => "Meta-analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Conclusion" ] 9 => array:3 [ "identificador" => "sec0100" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0105" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0110" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0115" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0120" "titulo" => "Conflicts of Interest" ] 11 => array:2 [ "identificador" => "xack280237" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-24" "fechaAceptado" => "2016-09-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec830164" "palabras" => array:4 [ 0 => "Actinic keratosis" 1 => "Treatment" 2 => "Photodynamic therapy" 3 => "Daylight photodynamic therapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec830163" "palabras" => array:4 [ 0 => "Queratosis actínicas" 1 => "Tratamiento" 2 => "Terapia fotodinámica" 3 => "Terapia fotodinámica con luz de día" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Actinic keratosis is a precursor lesion to the most common nonmelanoma skin cancer. Conventional photodynamic therapy (PDT) has been shown to be effective, but the procedure is time-consuming, can be very painful, and requires infrastructure. These shortcomings led to the emergence of daylight PDT. To obtain a global estimate of efficacy, we undertook a systematic literature review and performed a meta-analysis of the available evidence on the efficacy and safety of daylight PDT as compared to conventional PDT in the treatment of actinic keratosis and/or field cancerization. The conclusion is that the difference in efficacy is clinically negligible (global estimate of the mean response rate difference,–3.69%; 95% CI,–6.54% to–0.84%). The adverse effects of daylight PDT are mild and localized (79% of patients report no discomfort), and patients report less pain (P<.001). Daylight PDT gives good to excellent cosmetic results in more than 90% of patients, and patient satisfaction is greater (P<.001)." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La queratosis actínica es la lesión precursora de cáncer cutáneo no-melanoma más frecuente. La terapia fotodinámica convencional se ha empleado eficazmente pero requiere tiempo, infraestructuras y es en ocasiones muy dolorosa. En este contexto surge la terapia fotodinámica con luz de día (TFDLD). Con el objetivo de estudiar las evidencias disponibles que evalúan la eficacia y seguridad de la TFDLD frente a la terapia fotodinámica convencional en el tratamiento de pacientes con queratosis actínica/campo de cancerización, y obtener un estimador global de eficacia, realizamos una revisión sistemática de la literatura y un metaanálisis. Se concluye que la variación en eficacia entre ambas terapias es clínicamente irrelevante (estimador global de la diferencia de tasas de respuesta media:–3,69%, IC 95%:–6,54 a–0,84). Con TFDLD el dolor referido es menor (p<0,001), los efectos adversos locales y leves (el 79% no refiere molestias), los resultados cosméticos buenos-excelentes (>90% de los casos) y la satisfacción del paciente mayor (p<0,001)." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Tomás-Velázquez A, Redondo P. De la terapia fotodinámica convencional a la terapia fotodinámica con luz de día en el tratamiento de las queratosis actínicas: revisión sistemática y metaanálisis. Actas Dermosifiliogr. 2017;108:282–292." ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3122 "Ancho" => 2736 "Tamanyo" => 303619 ] ] "descripcion" => array:1 [ "en" => "Flow chart of the search, screening, and selection process for the trials finally reviewed and analyzed. RCT refers to randomized controlled trial." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1130 "Ancho" => 2373 "Tamanyo" => 110713 ] ] "descripcion" => array:1 [ "en" => "Forest plot comparing response rates for conventional versus daylight PDT according to per-protocol analysis. The figure shows that the CIs were below the noninferiority margins established a priori (20% by Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 15% by Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>). Thus, daylight PDT can be considered noninferior. PDT refers to photodynamic therapy and diff. to difference." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1113 "Ancho" => 2379 "Tamanyo" => 114426 ] ] "descripcion" => array:1 [ "en" => "Forest plot comparing response rates for conventional versus daylight PDT according to intention-to-treat analysis. The figure shows that the CIs were below the noninferiority margins established a priori (20% by Rubel et al.19<a class="elsevierStyleCrossRef" href="#bib0325">19</a> and 15% by Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a>). Thus, daylight PDT can be considered noninferior. PDT refers to photodynamic therapy and diff. to difference." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: AK, actinic keratosis; F, female; ITT, intention-to-treat analysis; M, male; MAL, methyl aminolevulinate; NS, not specified; PDT, photodynamic therapy; PP, per-protocol analysis; SPF, sun protection factor." "tablatextoimagen" => array:3 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Objective \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To compare conventional PDT to red light PDT to daylight PDT (response rates and adverse effects) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To evaluate the noninferiority of daylight PDT vs conventional PDT and intensity of pain caused \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To demonstrate the noninferiority of efficacy and the superiority of safety of daylight PDT vs conventional PDT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Journal and year of publication \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Br J Dermatol 2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Br J Dermatol 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">J Eur Acad Dermatol Venereol 2015 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Trial design \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, controlled, single blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase III trial, multicenter, randomized, controlled, single blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase III trial, multicenter, randomized, controlled, single blind \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Country \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Denmark \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Australia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">France, Germany, Spain, Switzerland, the Netherlands \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No. of centers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Analytic approach \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PP, ITT of efficacy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PP, ITT of efficacy  \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Follow-up, wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406648.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="left" valign="top" scope="col">Characteristics of the patient sample:</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No. of cases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">108 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age, range (mean) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">63–90 (78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42–90 (66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">47–91 (72.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex, M/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23/6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75/25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99/9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AK grade \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I,II,III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I,II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I,II \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Location \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Face, scalp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Face, scalp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Face, Scalp \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surface area treated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80cm2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Minimum 5 AKs, maximum 8×18cm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Minimum 5 AKs, maximum 6×16cm \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406650.png" ] ] 2 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " colspan="4" align="left" valign="top" scope="col">Characteristics of the PDT procedure used in the trials:</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">When administered \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">June–September, 2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">March–November, 2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">July–January, 2013–2014 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No. of sessions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sunscreen during daylight PDT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High SPF, without mineral screens \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High SPF, with chemical screens \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Photosensitizing agent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MAL 16% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MAL 16% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MAL 16% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incubation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30min in daylight PDT, 3h in conventional PDT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30min in daylight PDT, 3h in conventional PDT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30min in daylight PDT, 3h in conventional PDT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duration of exposure in daylight PDT, h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weather conditions during daylight exposure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sunny, partly cloudy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sunny, partly cloudy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Comfortable outdoor conditions, not raining \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406647.png" ] ] ] ] "descripcion" => array:1 [ "en" => "General Characteristics of the Trials Included in the Qualitative Analysis." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "fx1.jpeg" "imagenAlto" => 2541 "imagenAncho" => 3444 "imagenTamanyo" => 605687 ] ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Green filler indicates the information was given and was sufficient; blue, information given but was insufficient; red, information not given." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics Found in the 3 Trials Selected.<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>" ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wiegell et al.<a class="elsevierStyleCrossRef" href="#bib0290">12</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Results at 3 mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of 79% of AKs with daylight PDT and 71% with conventional PDT (P=.13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete response rates: PP, 89.2% with daylight PDT; 92.8% with conventional PDT (95% CI, −6.8% to −0.3%) ITT, 86.4% with daylight PDT; 89.9% with conventional PDT (95% CI, −6.6% to −0.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complete response rates: PP, 70% with daylight PDT; 74% with conventional PDT (95% CI, −9.5% to 2.4%) ITT, not specified (95% CI, −8.6% to 2.4%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Results at 6 mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not studied \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maintenance of complete response: 96% with daylight PDT; 96.6% with conventional PDT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not studied \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain score<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a>, mean (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2(1.9) with daylight PDT; 6.7 (2.2) with conventional PDT (P<.0001) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.8(1.2) with daylight PDT; 5.7 (2.3) with conventional PDT (P<.001) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.7 with daylight PDT; 4.4 with conventional PDT (P<.001) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other findings \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adverse effects common to both treatments: erythema, crusts Patient preference: 62% preferred daylight PDT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adverse effects by modality (% daylight PDT; % conventional PDT) Total (39%; 59%) Severe (0%; 0%) Interruption (0%; 0%) Skin reaction (24%; 30%) Erythema (2%; 5%) Phototoxicity (5%; 10%) Crust formation (9%; 9%) Bleeding (2%; 3%) Irritation (1%; 2%) Facial edema (1%; 0%) Itching (0%; 1%) Burning (0%; 2%) Edema (0%; 1%) Researcher's preference regarding tolerance: 48%, no preference 33.7%, daylight PDT; 18.3%, conventional PDT (P<.011) Clinical evaluation, at 12 wk 90% of treated lesions good or excellent Cosmetic results satisfactory and similar \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Adverse effects: 45.4% with daylight PDT; 61.1% with conventional PDT (erythema, crusts, burning sensation) Cosmetic results at 12 wk: good or excellent, and similar (98% with daylight PDT; 99.7% with conventional PDT) Patient preferences (daylight PDT; conventional PDT): Satisfaction (64.8%; 18.9%) Pain-free (91.3%; 22.3%) No discomfort (79.4%; 43.4%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406651.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Pain was scored on a numerical scale of 0 to 10. Abbreviations: AK, actinic keratosis; ITT, intention to treat; PDT, photodynamic therapy; PP, per protocol." ] ] ] "descripcion" => array:1 [ "en" => "Results of the Qualitative Analysis of the 3 Selected Trials." ] ] 6 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviation: PDT, photodynamic therapy." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rubel et al.<a class="elsevierStyleCrossRef" href="#bib0325">19</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lacour et al.<a class="elsevierStyleCrossRef" href="#bib0330">20</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Global Estimate \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Difference in per-protocol analysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3.6% 95% CI, −6.8% to −0.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−4% 95% CI, −9.5% to 2.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3.69% 95% CI, −6.54% to −0.84% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Difference in intention-to-treat analysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3.5% 95% CI, −6.6% to −0.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3.10% 95% CI, −8.6% to 2.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−3.40% 95% CI, −6.10% to −0.70% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1406649.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Differences in Response Rates Between Conventional and Daylight PDT." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:46 [ 0 => array:3 [ "identificador" => "bib0235" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D.E. 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Review

Switching From Conventional Photodynamic Therapy to Daylight Photodynamic Therapy For Actinic Keratoses: Systematic Review and Meta-analysis

De la terapia fotodinámica convencional a la terapia fotodinámica con luz de día en el tratamiento de las queratosis actínicas: revisión sistemática y metaanálisis

A. Tomás-Velázquez

Corresponding author

atomas.1@alumni.unav.es

Corresponding author.

, P. Redondo

Departamento de Dermatología, Clínica Universidad de Navarra, Pamplona, Spain

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            "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical manifestations in frontal fibrosing alopecia&#46; A&#44; Receding hairline in the frontotemporal region&#44; extending to the retroauricular region&#46; B&#44; The skin in the region of alopecia shows surface scarring&#44; with loss of follicular orifices&#44; uniform paleness&#44; and a vascular network&#46; C&#44; Trichoscopy image at the frontal hairline&#44; in which absence of follicular ostia&#44; erythema&#44; perifollicular scaling&#44; and branched capillaries can be observed&#46; D&#44; Trichoscopy image of the retroauricular region in which similar changes to those described above can be observed&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Forest plot comparing response rates for conventional versus daylight PDT according to intention-to-treat analysis&#46; The figure shows that the CIs were below the noninferiority margins established a priori &#40;20&#37; by Rubel et al&#46;19<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 15&#37; by Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&#41;&#46; Thus&#44; daylight PDT can be considered noninferior&#46; PDT refers to photodynamic therapy and diff&#46; to difference&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Actinic keratosis &#40;AK&#41; is the most common precancerous skin tumor&#46; 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&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">1&#44;2</span></a> The lifetime risk of AK is 50&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">3</span></a> and this condition is among the most frequent reasons patients visit a dermatologist&#44; absorbing both time and resources&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">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&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">4&#44;5</span></a> 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&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">6</span></a> 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&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Conventional photodynamic therapy &#40;PDT&#41;&#44; used increasingly for over 10 years&#44; has become the treatment of choice for AK and field cancerization<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">7</span></a> given response rates of 86&#37; clearance at 4 months&#44; recurrence rates under 20&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">8</span></a> and excellent cosmetic results&#46; Incubation with a photosensitizing agent increases the production of selective protoporphyrin IX &#40;PpIX&#41; by tumor cells&#46; Exposure to light at the appropriate wavelength and dose in the presence of oxygen induces oxidation and cell death&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">9</span></a> This treatment requires dedicated staff&#44; facilities&#44; irradiation equipment&#44; and time&#46; However&#44; the main problem with this modality is pain&#44; and even though steps are taken to alleviate it&#44; treatment must occasionally be interrupted&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Daylight-mediated PDT&#44; which uses direct and air-reflected sunlight&#44; has emerged in response to the need for a simpler and less painful therapy&#46; A role for using natural light to induce a reaction in photosensitized skin was suggested in 2006&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">10</span></a> but it was in a 2007 publication that Batchelor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">11</span></a> first documented the use of this modality and its effectiveness in considerably reducing the total number of AKs on a patient&#39;s scalp&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Later&#44; 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&#46; They found no significant differences in efficacy between the 2 treatments &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;13&#41;&#46; Erythema and crust formation were also similar&#44; but pain was significantly greater when red light was used &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#46; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> A 2009 publication showed that a lower concentration &#40;8&#37;&#41; of the photosensitizing agent &#40;methyl aminolevulinate &#91;MAL&#93;&#41; than the one used in the earlier studies &#40;16&#37;&#41; could also be effective&#44; and they established 8<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> as the minimum effective light dose&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">13</span></a> The group then undertook a multicenter trial that was published in 2011&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">14</span></a> Two durations of daylight exposure &#40;1&#46;5<span class="elsevierStyleHsp" style=""></span>hours and 2&#46;5<span class="elsevierStyleHsp" style=""></span>hours&#41; were found to have statistically similar outcomes &#40;response rates&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;7&#59; pain intensity&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;94&#41; and adverse effects&#46; Seventy-two percent of patients in the trial were satisfied with daylight PDT&#46; A trial by another group concluded that although the response to daylight PDT was significantly greater when AK was mild &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#44; 86&#37; of type II AKs and 94&#37; of type III AKs nonetheless cleared completely or were reduced to a lower grade&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> Other authors reported similar results in Switzerland&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">16</span></a> Brazil&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">17</span></a> and southern Italy&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">18</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">After several years of uncertainty and lack of consensus about daylight PDT&#44; given the scarcity of evidence&#44; new phase III clinical trials were recently published&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> 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&#46; We evaluated the consistency and quality of the trials published and meta-analyzed the results to obtain a global estimate of effect&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis took into consideration the Preferred Reporting Items for Systematic Reviews and Meta-Analyses &#40;PRISMA recommendations&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">21</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Sources and Search Strategy</span><p id="par0040" class="elsevierStylePara elsevierViewall">Our sources of articles were MEDLINE&#44; the Cochrane Central Register of Controlled Trials&#44; the Web of Science&#44; and the registry of clinical trials of the US National Institutes of Health<span class="elsevierStyleItalic">&#46;</span></p><p id="par0045" class="elsevierStylePara elsevierViewall">The first search was done in June 2015&#46; The same search strategy was repeated in December 2015&#46; We used the following search terms&#58; <span class="elsevierStyleItalic">actinic keratoses</span> and <span class="elsevierStyleItalic">daylight photodynamic therapy</span>&#46; In the PubMed portal we added the term <span class="elsevierStyleItalic">randomized</span> or <span class="elsevierStyleItalic">randomised</span>&#46; No year or language restrictions were introduced&#44; and we read articles in both English and Spanish&#46; Full texts were accessed&#46; In addition&#44; we consulted experts and contacted one of the authors of the included studies to be sure we had not missed any important trials and to check that we had understood certain trial characteristics and analyzed them correctly&#46; We also consulted the gray literature to avoid publication bias&#46; The reference lists of all studies found were also reviewed&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Inclusion Criteria</span><p id="par0050" class="elsevierStylePara elsevierViewall">Inclusion was restricted to randomized controlled trials that evaluated the efficacy or noninferiority of daylight PDT versus conventional PDT in humans with AK&#46; This decision was based on the need to determine that daylight PDT is no less effective than conventional PDT and that it was better tolerated by the patient&#44; being simpler and more cost-effective&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Any population&#44; age group&#44; or body area exposed could be included&#46; Duration of follow-up was not a selection criterion&#44; and no restrictions were placed on the PDT protocol followed&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Article Selection Process&#44; Data Items and Extraction&#44; and Analysis of Quality of Trial Design</span><p id="par0060" class="elsevierStylePara elsevierViewall">We first completed the search&#44; evaluated the studies&#44; and synthesized their results&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The 2 main variables established a priori were lesion response rate and pain caused by the procedure&#46; Other variables&#44; such as AK grade&#44; other adverse effects&#44; patient satisfaction&#44; cosmetic results&#44; duration of follow-up&#44; statistical approach&#44; or blinding were also taken into account&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The search was unblinded with regard to authors&#44; journals&#44; and research facility&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">We consulted the Jadad scoring system for randomized trials&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> and our critical analysis was based on the CONSORT reporting guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Statistical Analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The meta-analyzed variable was the percentage of lesions with a complete response &#40;number of fully cleared lesions as a percentage of the number treated&#41; at week 12&#46; We calculated the difference between the mean rate of response to daylight PDT and the mean rate of response to conventional PDT&#59; we also calculated 95&#37; CIs&#46; A fixed-effects meta-analysis was performed according to the inverse variance method&#46; Both per-protocol &#40;PP&#41; and intention-to-treat &#40;ITT&#41; analyses were carried out&#46; Noninferiority of efficacy of daylight versus conventional PDT was demonstrated based on the expert-established thresholds for a clinically significant difference in effect between treatments&#58; 20&#37; according to Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 15&#37; according to Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Trial Selection</span><p id="par0085" class="elsevierStylePara elsevierViewall">Twenty articles were identified in the MEDLINE search&#44; 14 in the Cochrane database&#44; and 11 in the Web of Science&#46; Two more gray literature articles were found&#44; for a total of 47 articles in all&#46; Twenty repeated titles were discarded&#46; Of the 27 remaining&#44; 21 were discarded because they clearly failed to meet the inclusion criteria&#46; Four compared aspects of PDT that were not of interest<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">24&#8211;27</span></a> &#40;photosensitizing agents vs placebo&#44; effectiveness of different photosensitizing agents&#44; artificial daylight vs red light-emitting diodes &#91;LED&#93; vs daylight vs white LED&#41;&#44; 9 were not randomized trials &#40;3 expert consensus reports or international association opinions&#44;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">28&#8211;30</span></a> 3 qualitative reviews&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">17&#44;31&#44;32</span></a> 1 retrospective case series&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">16</span></a> 1 letter to the editor&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">33</span></a> and 1 conference summary<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a>&#41;&#46; The remaining 8 articles also discussed issues different from the objective of our study &#40;the use of different photosensitizing agents&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> photosensitizer concentration required for effective daylight PDT&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> cost-effectiveness of daylight PDT versus LED PDT&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> fractional ablative laser treatment in combination with daylight PDT&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">38</span></a> effect of applying a sun screen to reduce inflammation after daylight PDT&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> effect of weather on daylight PDT in Australia&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">40</span></a> PDT results in transplanted patients&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">41</span></a> and PDT for head and neck tumors<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">42</span></a>&#41;&#46; Following in-depth study of the 6 remaining articles&#44; 3 more were excluded because they did not have the aims required for inclusion&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">13&#8211;15</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Finally&#44; 3 randomized trials comparing daylight PDT to conventional PDT were included in this systematic review&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">12&#44;19&#44;20</span></a> One of them<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> was excluded from the meta-analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Trial and Participant Characteristics</span><p id="par0095" class="elsevierStylePara elsevierViewall">The characteristics of all 3 trials qualitatively reviewed are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">These 3 all treated 2 symmetrical areas in the same patients &#40;intraindividual comparison&#41; and used MAL as the photosensitizing agent&#46; After application of MAL&#44; daylight exposure of 1 of the areas started before 30<span class="elsevierStyleHsp" style=""></span>minutes had elapsed&#59; exposure continued for 2<span class="elsevierStyleHsp" style=""></span>to 2&#46;5<span class="elsevierStyleHsp" style=""></span>hours&#46; On the comparator area&#44; the photosensitizer was left incubating for 3<span class="elsevierStyleHsp" style=""></span>hours&#44; after which the skin was exposed to red light&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Trial Quality</span><p id="par0105" class="elsevierStylePara elsevierViewall">The results of our analysis of quality based on the CONSORT reporting guidelines for randomized clinical trials<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> were as follows&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The method used to measure adverse effects could have been made more explicit in the study by Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> These authors could also have explained their inclusion criteria more specifically and added a table showing patients&#8217; baseline characteristics&#46; In addition&#44; they did not specify how the randomization sequence was generated&#44; how researchers were blinded&#44; or whether the dermatologist who assessed the response was blinded&#46; CIs were not calculated and limitations were not listed&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The other 2 trials&#44; published in 2014 and 2015&#44; shared the same design features&#46; They were randomized investigator-blinded controlled trials lasting 24 weeks &#40;Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a>&#41; and 12 weeks &#40;Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&#41;&#46; They both compared intraindividual efficacy &#40;noninferiority&#41; and safety &#40;superiority in terms of less pain&#41; of daylight PDT versus conventional PDT for facial&#47;scalp AK&#46; Their aims&#44; the design&#44; and criteria were clear and specific&#46; Tables describing the sample and interventions were provided&#44; and the authors explained how variables were assessed&#46; Statistical power was reported and the randomization and blinding procedures were explained&#46; They included both PP and ITT analyses&#44; calculated 95&#37; CIs&#44; described adverse effects&#44; and listed limitations &#40;simple blinding&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> the difficulty of generalizing findings because of climate differences&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and the follow-up time<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&#41;&#46; Both complied with ethical standards&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Only the researchers were blinded in all 3 trials&#46; Pain is a subjective&#44; patient-reported variable and a patient&#39;s answers might change if the aim of the study and treatment assignment is acknowledged&#44; possibly biasing the information that can be obtained&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The information in each of the studies is summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">All 3 trials were registered at clinicaltrials&#46;gov<span class="elsevierStyleItalic">&#46;</span></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Trial Results</span><p id="par0135" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the findings of each of the 3 trials reviewed&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Efficacy</span><p id="par0140" class="elsevierStylePara elsevierViewall">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> found that the 2 modalities had statistically similar levels of efficacy &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;13&#41; and saw that response to daylight PDT did not vary with light intensity&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Rubel et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> who established 20&#37; as the margin of difference to demonstrate noninferiority&#44; found that the rate of complete response to daylight PDT &#40;89&#46;2&#37;&#41; was not statistically inferior to the response to conventional PDT &#40;92&#46;8&#37;&#41; at 12 weeks &#40;difference&#44;&#8211;3&#46;6&#37;&#59; 95&#37; CI&#44; &#8722;6&#46;8&#37; to &#8722;0&#46;3&#37;&#41;&#46; Moreover&#44; clearance was maintained by 96&#37; of the mild lesions at 24 weeks&#46; The findings of Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> were consistent with the other 2 trials&#46; Using a noninferiority margin of 15&#37;&#44; they observed complete response rates of 70&#37; for daylight PDT and 74&#37; for conventional PDT &#40;difference&#44;&#8211;4&#37;&#59; 95&#37; CI&#44; &#8722;9&#46;5&#37; to 2&#46;4&#37;&#41;&#46; They also concluded that daylight PDT was effective in different weather conditions &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Thus&#44; daylight PDT is effective and not inferior to conventional PDT&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patient-Reported Pain</span><p id="par0155" class="elsevierStylePara elsevierViewall">Pain was significantly greater in the area treated with conventional PDT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41; in the trial of Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a>&#59; although that result was unrelated to the level of PpIX fluorescence &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;065&#41;&#44; it was related to the effective light dose received &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;041&#41;&#46; Patients in the Australian<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and European<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> trials found daylight PDT to be nearly painless and certainly less painful than conventional PDT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Adverse Effects</span><p id="par0160" class="elsevierStylePara elsevierViewall">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> reported that erythema and crusts formed after both the daylight and conventional PDT treatments to a statistically similar degree and that the effects did not differ between treatment areas in 38&#37; of the patients&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Adverse effects in the phase III trials<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> were all dermatologic and mild&#46; The most common effect was a skin rash&#44; and in one of the trials 79&#37; of patients treated with daylight PDT were not inconvenienced by any adverse effect&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Thus&#44; daylight PDT does not have adverse effects that cause discomfort to patients&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Patient Satisfaction</span><p id="par0175" class="elsevierStylePara elsevierViewall">Sixty-two percent of the patients treated by Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> preferred daylight PDT&#46; Satisfaction with this modality was also greater &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; in the Australian trial&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> In the European trial&#44; 64&#46;8&#37; of the patients were highly satisfied with daylight PDT &#40;vs 18&#46;9&#37; with conventional PDT&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Cosmetic Results</span><p id="par0180" class="elsevierStylePara elsevierViewall">Cosmetic results after both treatment modalities were rated good or excellent by 90&#37; to 99&#46;7&#37; of the patients in the 2 phase III trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Meta-analysis</span><p id="par0185" class="elsevierStylePara elsevierViewall">We meta-analyzed the results of only the 2 phase III trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> The earliest trial reviewed<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> was excluded from the meta-analysis because it used a phase II design whose objective was mainly photobiologic&#44; to open doors to the use of this modality by demonstrating the continuous and effective production of PpIX in daylight&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The 2 later trials included a total of 186 patients in the PP analysis and 208 in the ITT analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> A total of 4668 AKs were treated&#44; 2336 with daylight PDT and 2332 with conventional PDT&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The difference between response rates &#40;PP analysis&#41; was 3&#46;6&#37; in the Australian trial<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 4&#37; in the European<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> one&#46; The global estimate of the mean response rate difference was &#8722;3&#46;69&#37; in favor of conventional PDT&#46; Because the estimate of effect size in the Australian trial was closer to the estimated effect derived from meta-analysis&#44; greater weight was assigned to this trial &#40;77&#46;02&#37; vs 22&#46;98&#37; to the European trial&#41;&#46; The <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> test result was 0&#46;0&#37;&#44; as heterogeneity was very low between the 2 trials&#44; whose design and results were similar &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Therefore&#44; we did not perform further measures of heterogeneity&#46; The results of the ITT analysis were similar&#44; yielding a global effect estimate of 3&#46;4&#37; in favor of conventional PDT &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Thus&#44; although conventional PDT is associated with higher response rates than daylight PDT&#44; the difference is not clinically important&#44; as it is less than the difference margins &#40;20&#37; and 15&#37;&#41; established a priori&#46; The 95&#37; CIs of the global effect estimates ranged from &#8722;6&#46;54&#37; to &#8722;0&#46;84&#37; and &#8722;6&#46;10&#37; to &#8722;0&#46;70&#37; in the PP and ITT analyses&#44; respectively&#46; Therefore&#44; daylight PDT can be considered noninferior to conventional PDT&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0205" class="elsevierStylePara elsevierViewall">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&#46; The strictest of the expert-proposed definitions of a clinically important difference is 15&#37;&#46; The global effect estimate of&#8211;3&#46;9&#37;&#44; favoring conventional PDT&#44; was within this margin and its 95&#37; CI was &#8722;6&#46;54&#37; to &#8722;0&#46;84&#37;&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">One factor that might contribute to the lower daylight PDT response rates of 89&#46;2&#37;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 70&#37;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> &#40;vs 92&#46;8&#37;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 74&#37;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> for conventional PDT&#41; is the lack of clinical control over the amount of daylight exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> This theory is supported by a larger difference in effect&#44; in favor of the conventional modality&#44; in the PP analysis in comparison with the ITT analysis since patients interrupted conventional PDT because of pain&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">The differences in efficacy and adverse effects between the trial of Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> and the Australian<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and European<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> trials may be attributable to the phase design&#44; the first being a phase II trial and the other 2 being phase III trials&#46; The first trial sought preliminary information to support efficacy&#44; the presence of a dose-response pattern&#44; and safety&#44; whereas the 2 more recent trials compared the efficacy of the new modality to one that was already available&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Furthermore&#44; 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&#44; for the sake of patient comfort&#44; and cold &#40;below 10<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#44; to guarantee proper generation of PpIX&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a> Likewise&#44; adverse effects&#44; which are all superficial and mild&#44; do not differ greatly between daylight and conventional PDT&#46; Subjective reports of pain on a scale of 0 to 10&#44; however&#44; were significantly lower with daylight PDT in all 3 of the trials we reviewed&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">12&#44;19&#44;20</span></a> Thus&#44; patients tolerate daylight PDT better&#44; prefer this modality&#44; and express greater satisfaction with it&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">AK is a prevalent and recurring problem that may progress to squamous cell carcinoma&#46; Therefore&#44; treatments that act quickly and whose effect is maintained are sought&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> Given that daylight PDT is noninferior with regard to efficacy but is better tolerated than conventional PDT&#44; the new modality has been said to offer &#8220;gain without pain&#46;&#8221;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">16</span></a> One recent study found that 70&#37; of clinicians agreed that the duration of therapy and local reactions diminished adherence to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">43</span></a> Daylight PDT addresses the problem of risk of malignancy in AK by offering a more cost-effective alternative<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> with savings in time&#44; staff&#44; material&#44; and infrastructure&#46; Nevertheless&#44; vigilance after approval of daylight PDT to treat AK is important&#46; 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&#44; where patients are often of advanced age&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">It is true that response rates are lower in higher grade AK &#40;grade I&#44; 75&#46;9&#37;&#59; grade II&#44; 61&#46;2&#37;&#59; and grade III&#44; 49&#46;1&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> However&#44; it is also true that all thick AKs become thinner after a single daylight PDT session&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> According to expert opinion&#44; grade III AKs that might be present in field cancerization can be treated&#44; even though it is assumed that their response will be less marked and that more sessions or adjuvant treatments may be needed&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Thus&#44; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Use of this modality in transplanted patients or other immunocompromised individuals can be taken under advisement&#44; but further study will be needed in this population&#44; which is particularly susceptible to the development of AK and nonmelanoma skin cancer&#46; We also lack evidence of the efficacy of daylight PDT on other skin lesions&#44; although anecdotal reports of its application in basal cell carcinoma&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">44</span></a> Bowen disease&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">45</span></a> and actinic cheilitis<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">46</span></a> have been published&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The trials we selected have certain design flaws&#44; such as the lack of specification of the randomization and blinding methods in the Danish study&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a> and the short duration of follow-up &#40;3 months&#41; in both that study and the European multicenter one&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a> However&#44; the Australian study found that outcomes were satisfactory at 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> Bias that might result from lack of patient blinding when pain is reported has already been mentioned&#44; but complete patient blinding in PDT is practically impossible&#46; Therefore&#44; the trials included in the meta-analysis can be considered to have been very well designed&#44; lending support to their internal validity and&#44; in consequence&#44; to the global estimate of efficacy&#46; The fact that only 2 trials could be included in the meta-analysis&#44; however&#44; makes it difficult to draw conclusions and reveals the need to continue to study daylight PDT&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">A difficulty we encountered was the lack of sufficient information on the intensity of reported pain and lack of access to data&#46; Such information would have been useful for calculating a global effect estimate of this adverse effect&#46; The differences found&#44; however&#44; show a high level of clinical significance in the analyzed trials&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19&#44;20</span></a> where pain ranged from &#8220;sometimes unbearable&#8221; to &#8220;practically painless&#8221; and the Wilcoxon test found daylight PDT to be significantly superior &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; in this respect&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">To avoid publication bias&#44; we searched for both published and unpublished trials on known databases&#44; reviewed reference lists&#44; and contacted experts in the management of daylight PDT&#46; The trials we found&#44; therefore&#44; seem to represent the scope of research on this topic&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">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&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusion</span><p id="par0265" class="elsevierStylePara elsevierViewall">Daylight PDT is not inferior to conventional PDT in the treatment of mild to moderate AK and field cancerization&#46; The efficacy of this modality does not depend on weather conditions and has been applied at different latitudes&#46; The procedure is practically painless&#44; is better tolerated than conventional PDT&#44; and does not have important adverse effects&#46; Cosmetic outcomes are very good and patient satisfaction is high&#46; Daylight PDT&#39;s profile of efficacy&#44; tolerability and safety will probably make this modality a treatment of choice for AK and field cancerization&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethical Disclosures</span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Protection of human and animal subjects</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Confidentiality of data</span><p id="par0275" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Right to privacy and informed consent</span><p id="par0280" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article&#46;</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflicts of Interest</span><p id="par0285" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Sources and Search Strategy"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Inclusion Criteria"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Article Selection Process&#44; Data Items and Extraction&#44; and Analysis of Quality of Trial Design"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Statistical Analysis"
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          "titulo" => "Results"
          "secciones" => array:5 [
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              "titulo" => "Trial Selection"
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            1 => array:2 [
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              "titulo" => "Trial and Participant Characteristics"
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              "titulo" => "Trial Quality"
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              "titulo" => "Trial Results"
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                  "identificador" => "sec0060"
                  "titulo" => "Efficacy"
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                  "titulo" => "Patient-Reported Pain"
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                  "titulo" => "Adverse Effects"
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                  "identificador" => "sec0075"
                  "titulo" => "Patient Satisfaction"
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                  "titulo" => "Cosmetic Results"
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              "titulo" => "Meta-analysis"
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          "titulo" => "Discussion"
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          "titulo" => "Conclusion"
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          "titulo" => "Ethical Disclosures"
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              "titulo" => "Confidentiality of data"
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              "identificador" => "sec0115"
              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflicts of Interest"
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          "titulo" => "Acknowledgments"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-06-24"
    "fechaAceptado" => "2016-09-17"
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        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Actinic keratosis"
            1 => "Treatment"
            2 => "Photodynamic therapy"
            3 => "Daylight photodynamic therapy"
          ]
        ]
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          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Queratosis act&#237;nicas"
            1 => "Tratamiento"
            2 => "Terapia fotodin&#225;mica"
            3 => "Terapia fotodin&#225;mica con luz de d&#237;a"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Actinic keratosis is a precursor lesion to the most common nonmelanoma skin cancer&#46; Conventional photodynamic therapy &#40;PDT&#41; has been shown to be effective&#44; but the procedure is time-consuming&#44; can be very painful&#44; and requires infrastructure&#46; These shortcomings led to the emergence of daylight PDT&#46; To obtain a global estimate of efficacy&#44; we undertook a systematic literature review and performed a meta-analysis of the available evidence on the efficacy and safety of daylight PDT as compared to conventional PDT in the treatment of actinic keratosis and&#47;or field cancerization&#46; The conclusion is that the difference in efficacy is clinically negligible &#40;global estimate of the mean response rate difference&#44;&#8211;3&#46;69&#37;&#59; 95&#37; <span class="elsevierStyleSmallCaps">CI</span>&#44;&#8211;6&#46;54&#37; to&#8211;0&#46;84&#37;&#41;&#46; The adverse effects of daylight PDT are mild and localized &#40;79&#37; of patients report no discomfort&#41;&#44; and patients report less pain &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Daylight PDT gives good to excellent cosmetic results in more than 90&#37; of patients&#44; and patient satisfaction is greater &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La queratosis act&#237;nica es la lesi&#243;n precursora de c&#225;ncer cut&#225;neo no-melanoma m&#225;s frecuente&#46; La terapia fotodin&#225;mica convencional se ha empleado eficazmente pero requiere tiempo&#44; infraestructuras y es en ocasiones muy dolorosa&#46; En este contexto surge la terapia fotodin&#225;mica con luz de d&#237;a &#40;TFDLD&#41;&#46; Con el objetivo de estudiar las evidencias disponibles que eval&#250;an la eficacia y seguridad de la TFDLD frente a la terapia fotodin&#225;mica convencional en el tratamiento de pacientes con queratosis act&#237;nica&#47;campo de cancerizaci&#243;n&#44; y obtener un estimador global de eficacia&#44; realizamos una revisi&#243;n sistem&#225;tica de la literatura y un metaan&#225;lisis&#46; Se concluye que la variaci&#243;n en eficacia entre ambas terapias es cl&#237;nicamente irrelevante &#40;estimador global de la diferencia de tasas de respuesta media&#58;&#8211;3&#44;69&#37;&#44; IC 95&#37;&#58;&#8211;6&#44;54 a&#8211;0&#44;84&#41;&#46; Con TFDLD el dolor referido es menor &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; los efectos adversos locales y leves &#40;el 79&#37; no refiere molestias&#41;&#44; los resultados cosm&#233;ticos buenos-excelentes &#40;&#62;<span class="elsevierStyleHsp" style=""></span>90&#37; de los casos&#41; y la satisfacci&#243;n del paciente mayor &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p></span>"
      ]
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    "NotaPie" => array:1 [
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as&#58; Tom&#225;s-Vel&#225;zquez A&#44; Redondo P&#46; De la terapia fotodin&#225;mica convencional a la terapia fotodin&#225;mica con luz de d&#237;a en el tratamiento de las queratosis act&#237;nicas&#58; revisi&#243;n sistem&#225;tica y metaan&#225;lisis&#46; Actas Dermosifiliogr&#46; 2017&#59;108&#58;282&#8211;292&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Flow chart of the search&#44; screening&#44; and selection process for the trials finally reviewed and analyzed&#46; RCT refers to randomized controlled trial&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Forest plot comparing response rates for conventional versus daylight PDT according to per-protocol analysis&#46; The figure shows that the CIs were below the noninferiority margins established a priori &#40;20&#37; by Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 15&#37; by Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&#41;&#46; Thus&#44; daylight PDT can be considered noninferior&#46; PDT refers to photodynamic therapy and diff&#46; to difference&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Forest plot comparing response rates for conventional versus daylight PDT according to intention-to-treat analysis&#46; The figure shows that the CIs were below the noninferiority margins established a priori &#40;20&#37; by Rubel et al&#46;19<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> and 15&#37; by Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&#41;&#46; Thus&#44; daylight PDT can be considered noninferior&#46; PDT refers to photodynamic therapy and diff&#46; to difference&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AK&#44; actinic keratosis&#59; F&#44; female&#59; ITT&#44; intention-to-treat analysis&#59; M&#44; male&#59; MAL&#44; methyl aminolevulinate&#59; NS&#44; not specified&#59; PDT&#44; photodynamic therapy&#59; PP&#44; per-protocol analysis&#59; SPF&#44; sun protection factor&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Objective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To compare conventional PDT to red light PDT to daylight PDT &#40;response rates and adverse effects&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To evaluate the noninferiority of daylight PDT vs conventional PDT and intensity of pain caused&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To demonstrate the noninferiority of efficacy and the superiority of safety of daylight PDT vs conventional PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Journal and year of publication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Br J Dermatol<br>2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Br J Dermatol<br>2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">J Eur Acad Dermatol Venereol<br>2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Trial design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; controlled&#44; single blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III trial&#44; multicenter&#44; randomized&#44; controlled&#44; single blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III trial&#44; multicenter&#44; randomized&#44; controlled&#44; single blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Denmark&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Australia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">France&#44; Germany&#44; Spain&#44; Switzerland&#44; the Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No&#46; of centers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Analytic approach&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PP&#44; ITT of efficacy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PP&#44; ITT of efficacy<br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Follow-up&#44; wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="left" valign="top" scope="col">Characteristics of the patient sample&#58;</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No&#46; of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">108&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age&#44; range &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">63&#8211;90 &#40;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&#8211;90 &#40;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47&#8211;91 &#40;72&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex&#44; M&#47;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">75&#47;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#47;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AK grade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#44;II&#44;III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#44;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#44;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Location&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Face&#44; scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Face&#44; scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Face&#44; Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Surface area treated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Minimum 5 AKs&#44; maximum 8<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>18<span class="elsevierStyleHsp" style=""></span>cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Minimum 5 AKs&#44; maximum 6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            2 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="left" valign="top" scope="col">Characteristics of the PDT procedure used in the trials&#58;</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">When administered&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">June&#8211;September&#44; 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">March&#8211;November&#44; 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">July&#8211;January&#44; 2013&#8211;2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No&#46; of sessions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sunscreen during daylight PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High SPF&#44; without mineral screens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High SPF&#44; with chemical screens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Photosensitizing agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MAL 16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MAL 16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MAL 16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incubation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>min in daylight PDT&#44; 3<span class="elsevierStyleHsp" style=""></span>h in conventional PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>min in daylight PDT&#44; 3<span class="elsevierStyleHsp" style=""></span>h in conventional PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>min in daylight PDT&#44; 3<span class="elsevierStyleHsp" style=""></span>h in conventional PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duration of exposure in daylight PDT&#44; h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weather conditions during daylight exposure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sunny&#44; partly cloudy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sunny&#44; partly cloudy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Comfortable outdoor conditions&#44; not raining&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">General Characteristics of the Trials Included in the Qualitative Analysis&#46;</p>"
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      ]
      4 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Green filler indicates the information was given and was sufficient&#59; blue&#44; information given but was insufficient&#59; red&#44; information not given&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Characteristics Found in the 3 Trials Selected&#46;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
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      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wiegell et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Rubel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lacour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Results at 3 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction of 79&#37; of AKs with daylight PDT and 71&#37; with conventional PDT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete response rates&#58;<br>PP&#44; 89&#46;2&#37; with daylight PDT&#59; 92&#46;8&#37; with conventional PDT<br>&#40;95&#37; CI&#44; &#8722;6&#46;8&#37; to &#8722;0&#46;3&#37;&#41;<br>ITT&#44; 86&#46;4&#37; with daylight PDT&#59; 89&#46;9&#37; with conventional PDT<br>&#40;95&#37; CI&#44; &#8722;6&#46;6&#37; to &#8722;0&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete response rates&#58;<br>PP&#44; 70&#37; with daylight PDT&#59; 74&#37; with conventional PDT<br>&#40;95&#37; CI&#44; &#8722;9&#46;5&#37; to 2&#46;4&#37;&#41;<br>ITT&#44; not specified<br>&#40;95&#37; CI&#44; &#8722;8&#46;6&#37; to 2&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Results at 6 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not studied&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Maintenance of complete response&#58; 96&#37; with daylight PDT&#59; 96&#46;6&#37; with conventional PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not studied&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain score<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>&#40;1&#46;9&#41; with daylight PDT&#59; 6&#46;7 &#40;2&#46;2&#41; with conventional PDT<br>&#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;8<span class="elsevierStyleHsp" style=""></span>&#40;1&#46;2&#41; with daylight PDT&#59; 5&#46;7 &#40;2&#46;3&#41; with conventional PDT<br>&#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;7 with daylight PDT&#59; 4&#46;4 with conventional PDT<br>&#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adverse effects common to both treatments&#58;<br>erythema&#44; crusts<br>Patient preference&#58;<br>62&#37; preferred daylight PDT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adverse effects by modality &#40;&#37; daylight PDT&#59; &#37; conventional PDT&#41;<br>Total &#40;39&#37;&#59; 59&#37;&#41;<br>Severe &#40;0&#37;&#59; 0&#37;&#41;<br>Interruption &#40;0&#37;&#59; 0&#37;&#41;<br>Skin reaction &#40;24&#37;&#59; 30&#37;&#41;<br>Erythema &#40;2&#37;&#59; 5&#37;&#41;<br>Phototoxicity &#40;5&#37;&#59; 10&#37;&#41;<br>Crust formation &#40;9&#37;&#59; 9&#37;&#41;<br>Bleeding &#40;2&#37;&#59; 3&#37;&#41;<br>Irritation &#40;1&#37;&#59; 2&#37;&#41;<br>Facial edema &#40;1&#37;&#59; 0&#37;&#41;<br>Itching &#40;0&#37;&#59; 1&#37;&#41;<br>Burning &#40;0&#37;&#59; 2&#37;&#41;<br>Edema &#40;0&#37;&#59; 1&#37;&#41;<br>Researcher&#39;s preference regarding tolerance&#58;<br>48&#37;&#44; no preference<br>33&#46;7&#37;&#44; daylight PDT&#59; 18&#46;3&#37;&#44; conventional PDT<br>&#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;011&#41;<br>Clinical evaluation&#44; at 12 wk<br>90&#37; of treated lesions good or excellent<br>Cosmetic results<br>satisfactory and similar&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Adverse effects&#58;<br>45&#46;4&#37; with daylight PDT&#59; 61&#46;1&#37; with conventional PDT &#40;erythema&#44; crusts&#44; burning sensation&#41;<br>Cosmetic results at 12 wk&#58;<br>good or excellent&#44; and similar &#40;98&#37; with daylight PDT&#59; 99&#46;7&#37; with conventional PDT&#41;<br>Patient preferences &#40;daylight PDT&#59; conventional PDT&#41;&#58;<br>Satisfaction<br>&#40;64&#46;8&#37;&#59; 18&#46;9&#37;&#41;<br>Pain-free &#40;91&#46;3&#37;&#59; 22&#46;3&#37;&#41;<br>No discomfort<br>&#40;79&#46;4&#37;&#59; 43&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Pain was scored on a numerical scale of 0 to 10&#46;</p> <p class="elsevierStyleNotepara" id="npar0015">Abbreviations&#58; AK&#44; actinic keratosis&#59; ITT&#44; intention to treat&#59; PDT&#44; photodynamic therapy&#59; PP&#44; per protocol&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Results of the Qualitative Analysis of the 3 Selected Trials&#46;</p>"
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      6 => array:8 [
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2017.03.007

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Year/Month	Html	Pdf	Total

2024 November	16	8	24
2024 October	113	39	152
2024 September	99	24	123
2024 August	130	48	178
2024 July	119	25	144
2024 June	109	37	146
2024 May	104	43	147
2024 April	83	29	112
2024 March	87	37	124
2024 February	77	32	109
2024 January	57	34	91
2023 December	70	15	85
2023 November	78	27	105
2023 October	87	32	119
2023 September	56	29	85
2023 August	45	12	57
2023 July	45	30	75
2023 June	60	32	92
2023 May	43	30	73
2023 April	35	22	57
2023 March	68	18	86
2023 February	57	23	80
2023 January	41	28	69
2022 December	58	34	92
2022 November	54	41	95
2022 October	27	27	54
2022 September	20	30	50
2022 August	53	38	91
2022 July	45	40	85
2022 June	33	23	56
2022 May	49	44	93
2022 April	51	47	98
2022 March	56	70	126
2022 February	44	40	84
2022 January	50	50	100
2021 December	54	47	101
2021 November	63	41	104
2021 October	92	67	159
2021 September	55	48	103
2021 August	79	42	121
2021 July	43	33	76
2021 June	54	37	91
2021 May	65	50	115
2021 April	128	53	181
2021 March	75	31	106
2021 February	67	28	95
2021 January	48	28	76
2020 December	48	24	72
2020 November	40	29	69
2020 October	28	21	49
2020 September	47	23	70
2020 August	39	22	61
2020 July	31	10	41
2020 June	34	25	59
2020 May	24	15	39
2020 April	33	21	54
2020 March	37	16	53
2020 February	10	2	12
2020 January	3	0	3
2019 December	3	0	3
2019 November	8	3	11
2019 September	7	0	7
2019 August	5	0	5
2019 July	5	0	5
2019 June	4	0	4
2019 May	5	1	6
2019 April	6	3	9
2019 March	1	0	1
2019 February	7	2	9
2019 January	4	0	4
2018 December	4	0	4
2018 November	3	0	3
2018 October	4	0	4
2018 September	6	0	6
2018 February	31	8	39
2018 January	32	10	42
2017 December	39	8	47
2017 November	32	12	44
2017 October	30	10	40
2017 September	30	7	37
2017 August	18	14	32
2017 July	23	9	32
2017 June	49	16	65
2017 May	72	52	124
2017 April	17	31	48

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