The combination of oral and topical photoprotection with a standardized Polypodium leucotomos extract is beneficial against actinic keratosis

This study describes a prospective, multicentre, randomized controlled, open‐label study with three arms aimed at studying the differences between: [Cnt], self‐administered sun protection; [T], topical treatment; and [TO], topical + oral treatment; for the management of Actinic Keratosis (AK) in a cohort of subjects of advanced age displaying severe actinic damage (SAD).

this approach with respect to its implementation is practical: most subjects do not apply the sunscreen correctly, or sufficiently, over time. Multiple lines of evidence indicate that an insufficient dose at first application and failure to reapply after elimination or removal of the filters from the skin due to sweating, friction, etc., are major risk factors for skin damage and the onset of cancer. This alone justifies the use of systemic (oral) photoprotectors, which complement topical photoprotection with generalized anti-oxidant activity, DNA protection and repair, protection of skin immunosurveillance, antiaging and anti-hyperpigmentation activities. For this reason, we sought to evaluate the effects of a specific topical formulations and the potential additional protection offered by oral photoprotection in high-risk subjects.
Actinic Keratosis (AK) is a chronic, recurrent, and frequent disease caused by prolonged exposure to the Sun. 1,2 It is a high prevalent disease in Caucasians, affecting over one-third of adults over 60 year-old individuals in Europe, and up to 60% in Australia. 3,4 AKs are considered as initial forms of squamous cell carcinoma (SCC). 5 They may evolve into invasive SCC through the progressive and sequential transformation of neoplastic intraepidermal keratinocytes, identified and classified as histopathological grade I, II, and III, or through early invasion of early (grade I) lesions that evolve into invasive tumors directly. 6 Thus, the risk of developing SCC positively correlates better with the number of AK lesions than the single lesion histological grade. 7 Also, apparently unaffected sun-exposed areas in patients with AK present skin alterations similar to AK region, defining the so-called cancerization field, a wide skin area prone to develop new AKs and non-melanoma skin cancer. 8,9 The fact that UV radiation present in sunlight is the main cause of the disease, photoprotection is necessary. In this respect, systemic photoprotection could provide useful additional protection, as suggested by a clinical trial showing that systemic photoprotection decreased the incidence of SCC. 10 However, the lack of systematic and robust data results in a lack of consensus regarding the use of sunscreens, which gives too much leeway to the criteria of the physician or dermatologist regarding the use of additional measures, such as oral photoprotectors in high-risk groups.
Here, we postulate that systemic (oral) photoprotection administered in a controlled, systematic manner, increases the efficiency of topical treatment in subjects with severe actinic damage. To address this, we follow up on a combination of clinical parameters, that constitute the basis of easy-to-use "photo score", and microscopic examination of the skin carried out by means of non-invasive technique (in vivo reflectance confocal microscopy (RCM)), for determining intensity of damage and efficacy of the intervention. 11 The hypothesis is that this photo score will improve in subjects receiving protocol-determined doses of a specific topical sunscreen containing a non-filtering botanical extract compared to control subjects that use sunscreen ad libitum; and that the addition of a regime of a systemic (oral) photoprotector in addition to the topical regime would improve the photo score even further.
We selected a photoprotector (Fernblock, also referred to as Polypodium leucotomos extract, abbreviated PLE) that is used both topically and orally. Fernblock (standardized PLE) is a natural substance with well-documented beneficial effects in terms of photoprotection [12][13][14] and systemic reduction of Cyclobutane Pyrimidine Dimer (CPD) production in the dark after UV exposure. 15 Its mechanism of action includes anti-oxidant and DNA repair ability 16,17 ; inhibition of t-UCA isomerization 18 ; and prevention of immune cell depletion upon UV irradiation. 14,17,19 To our knowledge, this is the first assessor-blind, controlled trial evaluating the photoprotective effect of PLE, topical or topical + oral in high-risk patients bearing severe actinic damage.

| Study aim
Here, we have evaluated the effects of different sun protection strategies, subjects displaying severe actinic damage (SAD) were randomly assigned to one of three groups: [Cnt] = general, nonspecific photoprotection measures as decided by the patients

| MATERIAL S AND ME THODS
The present study was reviewed and approved by the Ethical  diseases that might confuse the findings of the present study, e.g., LES, high-sensitivity photosensitivity, rosacea, etc.; age outside of the 60-85 years old range; inability to comprehend and thus provide formal consent for inclusion in the study or unable to follow the instructions provided to the different treatment groups; very limited photo exposure, e.g., subjects that do not leave their house; allergies and/or adverse reactions to the active principles, or adjuvants, of the topical and oral components of the formulations used in the study.

| Study design
This was a multi-center prospective, randomized, parallel-group, assessor-blinded trial. A total of 3 clinical assessments (at enrolment, t = 0; after 6 months, 6m; after 12 months, 12 m) were performed on each subject.

| Study outcomes
Additional parameters include: adverse events emerging during the study, related to the use of the products; skin color homogeneity at 6 and 12 months; visual assessment of the treated area and untreated areas; the degree of patient satisfaction and adherence to the study for 12 months. These last data were collected through a survey using a fillable form, which included questions regarding sun habits, photoprotection, and self-perception.

| Statistical analysis and sample size calculation
The hypothesis is that [T] and [TO] groups display a better clinical score of the analyzed parameters compared to the [Cnt] group.
Sample size calculation was carried out using with G*Power 3.0.10 software (17695343). Sample size calculation was complicated by the fact that reports on average AKASI scores for these patients are scant, and it is difficult to predict the degree of improvement caused by the treatments. Setting up an initial AKASI score average of 4.75, we estimated that a reasonable improvement threshold could be 20% (3.75). These parameters returned the following sta-  Finally, self-assessment of the subjects revealed differences in terms of self-perception (p < .001) and modification of photoprotection habits (p = .03).

| DISCUSS ION
The present study represents an initial characterization of the benefit of topical + oral supplementation in the management of AK.
Evaluation of objective parameters, such as AKASI, revealed an expected worsening of the condition in subjects of the control group, sunscreen use ad libitum, whereas improvements were observed in the group receiving specific topical treatment, and especially in  ance. 8 However, most studies focus on short-term clearance evaluated within 3 to 6 months after treatment. A recent pooled analysis of randomized controlled trials found that these results were not maintained in the long term, showing recurrence rates similar to most active interventions and were not superior to placebo. 26 Thus, an effective approach requires lesion and field treatment, followed by intervention intended to reduce lesion recurrence and, likely, squamous cell carcinoma development.
In this study, we showed two main points which could help in future AK management direction: 1. Sun-protection recommendation ad libitum (leaving the patient free to decide sunscreen quantity and quality) is not strongly effective in AK recurrence prevention, whereas a greater benefit is given by specific product recommendations and specific usage indications.
2. Combination of topical + oral photoprotection is significantly reducing AK recurrences and the need for further treatment.  study. In addition to the positive effect seen in sun-exposed skin, these data reinforce the observation that adjuvant treatment with topical and oral photoprotectors may be beneficial in patients undergoing phototherapy. 27 Why topical + oral photoprotection resulted more effective than It is important to acknowledge that the present study has some limitations. First, the groups are large enough to provide statistical power, but not sufficiently to make wider predictions. Another possible limitation of this approach is that, based on the design of the study, there is no formal proof that the ad libitum group followed the suggested application pattern with fidelity comparable to the other groups, which could affect skin hydration and hyperkeratosis. Also, skin phototype and other variables (specific lifestyle, additional dietary supplementation and unrelated medical treatments and procedures that could affect the outcome of the present protocol) would need to be taken into consideration. It is worth mentioning that the present study was impacted by the SARS-CoV-2 pandemic, which limited access to follow-up consultations and had some effect on the sun exposure of some patients due to lockdowns. Despite these issues, the present study showed that specific topical and topical + oral treatment with Fernblock (a biological non-filtering active principle endowed with protective activity when used topically or orally) of subjects already treated for AK and cancerization field (therefore at risk of recurrence), improved the control of AK and prevented new occurrences.

ACK N OWLED G M ENTS
The authors acknowledge funding from Difa Cooper, Italy. Open

Access Funding provided by Universita degli Studi di Roma La Sapienza
within the CRUI-CARE Agreement.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Salvador González is a consultant for Cantabria Labs, which produces Fernblock.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.