Daylight photodynamic therapy versus cryosurgery for the treatment and prophylaxis of actinic keratoses of the face - protocol of a multicenter, prospective, randomized, controlled, two-armed study

E Kohl, M Koller, F Zeman, R-M Szeimies, W G Philipp-Dormston, W Prager, P A Gerber, S Karrer, E Kohl, M Koller, F Zeman, R-M Szeimies, W G Philipp-Dormston, W Prager, P A Gerber, S Karrer

Abstract

Background: Photodynamic therapy with daylight (DL-PDT) is efficacious in treating actinic keratosis (AK), but the efficacy of field-directed, repetitive DL-PDT for the treatment and prophylaxis of AK in photodamaged facial skin has not yet been investigated.

Methods/design: In this multicenter, prospective, randomized, controlled, two-armed, observer-blinded trial, patients with a minimum of 5 mild-to-moderate AK lesions on photodamaged facial skin are randomly allocated to two treatment groups: DL-PDT with methyl aminolevulinate (MAL) and cryosurgery. In the DL-PDT group (experimental group), 5 treatments of the entire face are conducted over the course of 18 months. After preparation of the lesion and within 30 min after MAL application, patients expose themselves to daylight for 2 h. In the control group, lesion-directed cryosurgery is conducted at the first visit and, in the case of uncleared or new AK lesions, also at visits 2 to 5. The efficacy of the treatment is evaluated at visits 2 to 6 by documenting all existing and new AK lesions in the face. Cosmetic results and improvement of photoaging parameters are evaluated by means of a modified Dover scale. Primary outcome parameter is the cumulative number of AK lesions observed between visits 2 and 6. Secondary outcome parameters are complete clearance of AK, new AK lesions since the previous visit, cosmetic results independently evaluated by both patient and physician, patient-reported pain (visual analogue scale), patient and physician satisfaction scores with cosmetic results, and patient-reported quality of life (Dermatology Life Quality Index). Safety parameters are also documented (adverse events and serious adverse events).

Discussion: This clinical trial will assess the efficacy of repetitive DL-PDT in preventing AK and investigate possible rejuvenating effects of this treatment. (Trial registration: ClinicalTrials.gov Identifier: NCT02736760).

Trial registration: ClinicalTrials.gov Identifier: NCT02736760 . Study Code Daylight_01. EudraCT 2014-005121-13.

Keywords: AK; Cryosurgery; Daylight; Methyl aminolevulinate; PDT; Photorejuvenation; Prevention; Skin aging; Study protocol.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Institutional Review Board and the Ethics Committee of the University of Regensburg (Approval number: 15–112-0068).

Written informed consent is be obtained from each patient before enrolment.

Consent for publication

We have obtained consent to publish from the participant to report individual patient data (photograph).

Competing interests

M. Koller, F. Zeman, W. Prager, P.A. Gerber, E. Kohl: none.

S. Karrer is a member of scientific advisory boards of Galderma and receives honoraria for lectures from this company.

R.-M. Szeimies is member of advisory boards for Almirall, Biofrontera, Galderma, ISDIN, Leo Pharma, photonamic, and Pierre-Fabre. He has received speakers honoraria, and participated in clinical trials for the aforementioned companies.

W. G. Philipp-Dormston has been giving lectures, consulted, participated in advisory board meetings and in clinical studies by Allergan, Beiersdorf, Biofrontera, Galderma, Leo, L’Oréal, Merz and SkinCeuticals.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Potential study patient. Face of a potential study participant with Glogau Photodamage Classification Type III (advanced). Multiple visible AK, sallow skin discoloration with teleangiectasias and wrinkles

References

    1. Schaefer I, Augustin M, Spehr C, Reusch M, Kornek T. Prevalence and risk factors of actinic keratoses in Germany--analysis of multisource data. Journal of the European Academy of Dermatology and Venereology : JEADV. 2014;28(3):309–313. doi: 10.1111/jdv.12102.
    1. Flohil SC, van der Leest RJ, Dowlatshahi EA, Hofman A, de Vries E, Nijsten T. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam study. The Journal of investigative dermatology. 2013;133(8):1971–1978. doi: 10.1038/jid.2013.134.
    1. Siegel JA, Korgavkar K, Weinstock MA. Current perspective on actinic keratosis: a review. Br J Dermatol. 2017;177(2):350–8. doi: 10.1111/bjd.14852.
    1. Rowert-Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H, Sterry W, Stockfleth E. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007;156(Suppl 3):8–12. doi: 10.1111/j.1365-2133.2007.07860.x.
    1. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol. 1997;36(4):650–653. doi: 10.1016/S0190-9622(97)70265-2.
    1. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1(8589):795–797. doi: 10.1016/S0140-6736(88)91658-3.
    1. Quaedvlieg PJ, Tirsi E, Thissen MR, Krekels GA. Actinic keratosis: how to differentiate the good from the bad ones? European journal of dermatology : EJD. 2006;16(4):335–339.
    1. Diepgen TL, Brandenburg S, Aberer W, Bauer A, Drexler H, Fartasch M, John SM, Krohn S, Palfner S, Romer W, et al. Skin cancer induced by natural UV-radiation as an occupational disease-requirements for its notification and recognition. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2014;12(12):1102–1106.
    1. Werner RN, Stockfleth E, Connolly SM, Correia O, Erdmann R, Foley P, Gupta AK, Jacobs A, Kerl H, Lim HW, et al. Evidence- and consensus-based (S3) guidelines for the treatment of actinic keratosis - international league of dermatological societies in cooperation with the European dermatology forum - short version. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015;29(11):2069–2079. doi: 10.1111/jdv.13180.
    1. Wiegell SR, Fabricius S, Gniadecka M, Stender IM, Berne B, Kroon S, Andersen BL, Mork C, Sandberg C, Ibler KS, et al. Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study. Br J Dermatol. 2012;166(6):1327–1332. doi: 10.1111/j.1365-2133.2012.10833.x.
    1. Lacour JP, Ulrich C, Gilaberte Y, Von Felbert V, Basset-Seguin N, Dreno B, Girard C, Redondo P, Serra-Guillen C, Synnerstad I, et al. Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015;29(12):2342–2348. doi: 10.1111/jdv.13228.
    1. Rubel DM, Spelman L, Murrell DF, See JA, Hewitt D, Foley P, Bosc C, Kerob D, Kerrouche N, Wulf HC, et al. Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial. Br J Dermatol. 2014;
    1. Neittaanmaki-Perttu N, Karppinen TT, Gronroos M, Tani TT, Snellman E. Daylight photodynamic therapy for actinic keratoses: a randomized double-blinded nonsponsored prospective study comparing 5-aminolaevulinic acid nanoemulsion (BF-200) with methyl-5-aminolaevulinate. Br J Dermatol. 2014;171(5):1172–1180. doi: 10.1111/bjd.13326.
    1. Wiegell SR, Fabricius S, Stender IM, Berne B, Kroon S, Andersen BL, Mork C, Sandberg C, Jemec GB, Mogensen M, et al. A randomized, multicentre study of directed daylight exposure times of 1(1/2) vs. 2(1/2) h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol. 2011;164(5):1083–1090. doi: 10.1111/j.1365-2133.2011.10209.x.
    1. Zane C, Capezzera R, Sala R, Venturini M, Calzavara-Pinton P. Clinical and echographic analysis of photodynamic therapy using methylaminolevulinate as sensitizer in the treatment of photodamaged facial skin. Lasers Surg Med. 2007;39(3):203–209. doi: 10.1002/lsm.20470.
    1. Dover JS, Bhatia AC, Stewart B, Arndt KA. Topical 5-aminolevulinic acid combined with intense pulsed light in the treatment of photoaging. Arch Dermatol. 2005;141(10):1247–1252. doi: 10.1001/archderm.141.10.1247.
    1. Szeimies RM, Stockfleth E, Popp G, Borrosch F, Bruning H, Dominicus R, Mensing H, Reinhold U, Reich K, Moor AC, et al. Long-term follow-up of photodynamic therapy with a self-adhesive 5-aminolaevulinic acid patch: 12 months data. Br J Dermatol. 2010;162(2):410–414. doi: 10.1111/j.1365-2133.2009.09377.x.
    1. Wulf HC, Pavel S, Stender I, Bakker-Wensveen CA. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86(1):25–28.
    1. Togsverd-Bo K, Omland SH, Wulf HC, Sorensen SS, Haedersdal M. Primary prevention of skin dysplasia in renal transplant recipients with photodynamic therapy: a randomized controlled trial. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2015;15(11):2986–2990. doi: 10.1111/ajt.13358.
    1. Wennberg AM, Stenquist B, Stockfleth E, Keohane S, Lear JT, Jemec G, Mork C, Christensen E, Kapp A, Solvsten H, et al. Photodynamic therapy with methyl aminolevulinate for prevention of new skin lesions in transplant recipients: a randomized study. Transplantation. 2008;86(3):423–429. doi: 10.1097/TP.0b013e318180731e.
    1. Apalla Z, Sotiriou E, Chovarda E, Lefaki I, Devliotou-Panagiotidou D, Ioannides D. Skin cancer: preventive photodynamic therapy in patients with face and scalp cancerization. A randomized placebo-controlled study. Br J Dermatol. 2010;162(1):171–175. doi: 10.1111/j.1365-2133.2009.09492.x.
    1. Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic photorejuvenation. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al] 2002;28(8):742–744.
    1. Piccioni A, Fargnoli MC, Schoinas S, Suppa M, Frascione P, Ginebri A, Chimenti S, Peris K. Efficacy and tolerability of 5-aminolevulinic acid 0.5% liposomal spray and intense pulsed light in wrinkle reduction of photodamaged skin. The Journal of dermatological treatment. 2011;22(5):247–253. doi: 10.3109/09546634.2011.590791.
    1. Sanclemente G, Medina L, Villa JF, Barrera LM, Garcia HI. A prospective split-face double-blind randomized placebo-controlled trial to assess the efficacy of methyl aminolevulinate + red-light in patients with facial photodamage. Journal of the European Academy of Dermatology and Venereology : JEADV. 2011;25(1):49–58. doi: 10.1111/j.1468-3083.2010.03687.x.
    1. Kohl E, Karrer S. New developments in photodynamic therapy. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2013;64(5):363–369. doi: 10.1007/s00105-012-2513-x.
    1. Park MY, Sohn S, Lee ES, Kim YC. Photorejuvenation induced by 5-aminolevulinic acid photodynamic therapy in patients with actinic keratosis: a histologic analysis. J Am Acad Dermatol. 2010;62(1):85–95. doi: 10.1016/j.jaad.2009.06.025.
    1. Szeimies RM, Torezan L, Niwa A, Valente N, Unger P, Kohl E, Schreml S, Babilas P, Karrer S, Festa-Neto C. Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy. Br J Dermatol. 2012;167(1):150–159. doi: 10.1111/j.1365-2133.2012.10887.x.
    1. Orringer JS, Hammerberg C, Hamilton T, Johnson TM, Kang S, Sachs DL, Fisher G, Voorhees JJ. Molecular effects of photodynamic therapy for photoaging. Arch Dermatol. 2008;144(10):1296–1302. doi: 10.1001/archderm.144.10.1296.
    1. Issa MC, Pineiro-Maceira J, Vieira MT, Olej B, Mandarim-de-Lacerda CA, Luiz RR, Manela-Azulay M. Photorejuvenation with topical methyl aminolevulinate and red light: a randomized, prospective, clinical, histopathologic, and morphometric study. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al] 2010;36(1):39–48. doi: 10.1111/j.1524-4725.2009.01385.x.
    1. Bagazgoitia L, Cuevas Santos J, Juarranz A, Jaen P. Photodynamic therapy reduces the histological features of actinic damage and the expression of early oncogenic markers. Br J Dermatol. 2011;165(1):144–151. doi: 10.1111/j.1365-2133.2011.10270.x.
    1. Thai KE, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, Murrell D, Anderson C, Weightman W, Reid C, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43(9):687–692. doi: 10.1111/j.1365-4632.2004.02056.x.
    1. Zouboulis CC, Rohrs H. Cryosurgical treatment of actinic keratoses and evidence-based review. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2005;56(4):353–358. doi: 10.1007/s00105-004-0865-6.
    1. Krutmann J, Berking C, Berneburg M, Diepgen TL, Dirschka T, Szeimies M. New strategies in the prevention of actinic keratosis: a critical review. Skin Pharmacol Physiol. 2015;28(6):281–289. doi: 10.1159/000437272.
    1. Drago F, Ciccarese G, Parodi A. Nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2016;374(8):789–790. doi: 10.1056/NEJMc1514791.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe