Actinic keratosis (AK) is a common early in situ skin carcinoma caused by long-term sun exposure and usually develops on sun-exposed skin areas such as the face, ears, scalp, neck, forearms, and back of the hands. Left untreated, AK will progress to invasive squamous cell carcinoma (SCC) in approximately 10% of patients [1]. To reduce the risk of developing SCC, consensus guidelines recommend that clinicians routinely treat AK [2]. Treatment options include cryotherapy, topical treatments, curettage, surgical excision, and photodynamic therapy (PDT).

PDT is a cancer treatment modality combining light of appropriate wavelengths, a nontoxic photosensitizer, and sufficient molecular oxygen to generate reactive oxygen species and destroy target cells [3]. Over the last 15 years, PDT using 5-aminolevulinic acid (ALA) and PDT using methyl aminolevulinate (MAL) have been extensively investigated for the treatment of AK [4-8]. Topical application and incubation of ALA or MAL lead to selective accumulation of the endogenous photosensitizer protoporphyrin IX (PpIX) in the AK cells, and subsequent activation of PpIX by light of appropriate wavelengths induces, in the presence of oxygen, photochemical reactions leading to cell death [3].

Activation by red light using a total light dose of 37 J/cm² after 3 hours of incubation with MAL is a conventional protocol, usually referred to as PDT using the conventional protocol (C-PDT), that is approved and likely the most widely used in Europe for PDT of AK [9-11]. This protocol has been reported to be an effective PDT treatment option for AK and to result in similar response rates and improved cosmetic outcomes compared with standard therapies [9]. However, high pain scores have been demonstrated with this protocol, and concurrent use of cold air analgesia may be required to prevent discomfort [12,13].

Recently, several protocols involving an incubation with MAL for a maximum of 30 min followed by an activation by daylight for between 1 hour 30 min and 2 hours 30 min have been investigated [14-17]. From a European consensus [18], using a 2-hour daylight activation within 30 min after MAL application leads to a protocol (photodynamic therapy using the daylight European consensus protocol [D-PDT]) as effective as and better tolerated by patients than C-PDT. This better tolerability results from the maximum of 30 min for MAL incubation and the subsequent continuous activation of small amounts of PpIX. Nonetheless, using daylight as the irradiation source is not realistic for all weather conditions [19].

New protocols designed to be as effective as C-PDT, as nearly painless as D-PDT, and usable all year round are therefore emerging. Among these alternative protocols are the Flexitheralight protocol that we have recently published [20,21] and the Phosistos protocol (PDT using the Phosistos protocol [P-PDT]) that is discussed in this study. Developed within the Phosistos project supported by the European Commission under the Competitiveness and Innovation Framework Programme (Project identifier: CIP-ICT-PSP-2013-7-621103), P-PDT uses a 30-min MAL incubation followed by 2 hours and 30 min of irradiation with a light-emitting, fabric-based device. Due to the short incubation time, P-PDT should be as nearly painless as D-PDT. Furthermore, from a recent study that discusses potential PDT overtreatment when using some protocols including C-PDT [22], P-PDT with a total light dose almost 3 times lower than that of C-PDT could prove noninferior in efficacy. Moreover, the high flexibility of the light-emitting, fabric-based device ensures an optimal irradiation of the treatment area, which is not the case with the rigid flat light sources used in C-PDT.

The aim of this randomized, controlled, multicenter, intra-individual, noninferiority study is to assess the efficacy and tolerability of P-PDT compared with those of C-PDT in treating patients with AK of the forehead and scalp.

This study is a randomized, controlled, multicenter, intra-individual, noninferiority study comparing P-PDT versus C-PDT in the treatment of AK of the forehead and scalp. The study was conducted at 2 investigational sites: the department of dermatology at the Lille University Hospital in France and the Klinikum Vest in Germany.

Recruitment is closed and data collection is completed. Data analysis is ongoing and is expected to be completed in the first half of 2019.

This study was performed in accordance with the ethical principles of the Declaration of Helsinki (2008) and the International Conference on Harmonization Good Clinical Practice guidelines. The study design was reviewed and approved by the French National Agency for the Safety of Medicines and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé; authorization number: 2016-A00010-51), the French Ethics Committee (Comités de Protection des Personnes, CPP; authorization number: CPP 03/008/2016), the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte; authorization number: 2015_79 1.1), and the ethics committee of the University of Münster (Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität; approval number: 2016-513-f-M).

Patients were recruited from the patient population of the investigational sites.

The inclusion and exclusion criteria for patients to be included and excluded in the study are provided in Textboxes 1 and 2, respectively.

All patients received oral and written information before signing informed consent forms and subsequently entering the study.

P-PDT includes application of MAL cream under transparent occlusive dressing immediately followed by the installation on the patient’s head and turn-on of a light-emitting, fabric-based device for 3 hours. This device consists of a power control unit delivering 635-nm red light to a fiber optic–based fabric lining the inside of a cap (Texinov, Saint-Didier-de-la-Tour, France; Figure 1). The device, classified as exempt risk group according to IEC (International Electrotechnical Commission) 60601-2-57/2012, is configured to automatically start a 1.3mW/cm² irradiation 30 min after it is turned on (resulting in an incubation time of 30 min) and to stop 2 hours and 30 min later (resulting in a light dose of 12 J/cm²).

The primary objective of the study is to assess the noninferiority, in terms of efficacy at 3 months, of P-PDT compared with C-PDT. Outcome for the primary objective is the lesion complete response rate at 3 months.

The secondary objectives are as follows:

The corresponding outcomes are as follows:

The lesion complete response (“complete response” and “incomplete response”) and the skin appearance were clinically assessed by the investigators.

The study flowchart is shown in Table 1. After screening, patients entering the study had to come to the investigational site for 1 treatment visit (V1) and 3 evaluation visits (V2, V3, and V4). In case of recurrent AK at the 3-month evaluation visit (V3), patients had a second treatment visit within the 3 following weeks (V3bis).

On the day of treatment (V1), 10 to 14 AK were located, graded, photographed, and divided into 2 areas (area A and area B) similar to each other in terms of number and grade of AK. The location of each AK was marked on plastic sheets. Randomization was then performed by opening the next envelope in sequence. This envelope specified the protocol that each area had to receive: either P-PDT for area A and C-PDT for area B or C-PDT for area A and P-PDT for area B. In both cases, P-PDT (30-min MAL incubation followed by 2.5 hours of irradiation) was performed first, so that the 3-hour MAL incubation required for C-PDT was achieved after P-PDT was completed.

Both the areas were prepared by removing crusts, gently scraping the lesion surface, and applying MAL cream (Metvixia, Galderma, France) under a transparent occlusive dressing (Tegaderm, 3M, London Ontario, Canada) to the AK and surrounding normal skin (5-10 mm margin). An aluminum foil was placed over the transparent occlusive dressing, which covered the area randomized to receive C-PDT. The device involved in P-PDT was immediately set up and turned on. After 3 hours, P-PDT was completed as described in the Phosistos Protocol section. The device involved in P-PDT was removed, and the MAL cream was washed off with saline solution. The patient rated his pain on a pain scale. The area that just received P-PDT was then protected with aluminum foil, whereas an Aktilite CL128 lamp (Galderma SA, Lausanne, Switzerland) was placed 5 to 8 cm away from the other area and programmed to deliver 37 J/cm² in 7 to 10 min. At the end of C-PDT, the corresponding pain level was rated by the patient, who also completed the DLQI and the satisfaction questionnaire.

A total of 7 days after the treatment day (V2), patients were invited to report adverse effects/reactions and to complete the DLQI and the satisfaction questionnaire.

The treatment response was assessed 3 months after the treatment (V3) by the investigators by comparison with the photographs at the treatment day (V1). An investigator’s assessment of the skin appearance followed by the determination of the resulting cosmetic outcome was also performed. The DLQI and the satisfaction questionnaire were completed by patients. In case of recurrent AK, these latter were counted, graded, and photographed, and a second treatment visit, identical to the above-described first treatment (V1), was scheduled within 3 weeks after V3 (V3bis).

The last follow-up visit (V4) was performed 6 months after V1. During this visit, the treatment response and the cosmetic outcome were investigator-assessed by comparison with the photographs and the skin appearance at V1, respectively. The patients were asked to complete the DLQI and the satisfaction questionnaire.

Note that any AK appearing between V1 and V4 was not included in the assessment of the study outcomes.

Patients were randomly allocated to 1 of the 2 treatment options (either P-PDT for area A and C-PDT for area B or C-PDT for area A and P-PDT for area B) in a 1:1 ratio. The randomization sequence with stratification by treatment center in blocks of 4 was generated by an independent statistician using the PROC PLAN procedure of SAS (SAS Institute Inc, Cary, North Carolina, USA) and transferred to a sequence of sealed, opaque, and consecutively numbered envelopes. When a patient entered the study, randomization was performed by opening the next envelope in sequence.

The study is unblinded; both investigators and patients are aware of the treatment allocation.

All patient data were collected using an electronic case report form according to Good Clinical Practice and Standard Operating Procedures. Data collection was regularly monitored by a clinical research associate. Any deviation from the protocol was noted and the reason for the deviation documented. Any data inconsistency was brought to the attention of the clinical team and investigational site personnel (if required, data queries were sent). Resolutions to these data inconsistencies were reflected in the database.

The recruitment is closed and the clinical investigations are complete (Figure 2). Of the 47 recruited patients, 1 withdrew consent and did not receive any treatment protocol. A total of 46 patients were, therefore, treated with P-PDT on 1 area (for a total of 285 AK) and with C-PDT on the contralateral area (for a total of 285 AK). All these patients were evaluated at 3 months. Due to recurrent AK, 19 patients were required to undergo a second treatment visit. One of these patients dropped out because of fear of pain as intense as that experienced with C-PDT during the first treatment visit. As a result, 18 patients were retreated and 45 patients completed the study at 6 months.

All treated patients were men, and their mean age was 72.2 years. A total of 63% (29/46) of these patients had a Fitzpatrick skin type of II (Table 2). Whatever the protocol, approximately 45% of the AK were grade I and 55% were grade II (Table 3).

Data analysis is ongoing, and statistical results are expected to be available in the first half of 2019.