Photodynamic Therapy for Field Cancerization in the Skin: Where Do We Stand?
Keywords:
photodynamic therapy, skin-field cancerization, PDT, actinic keratosis, AKAbstract
Introduction: Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized skin.
Objectives: Our review aims to present the up-to-date literature on skin field cancerization using PDT employing different topical photosensitizers, modified light delivery protocols and combination treatments to obtain excellent efficacy and safety in everyday clinical practice.
Methods: We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library, Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND photodynamic therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness OR pain OR tolerability) for studies published until February 2023.
Results: Advantages of PDT compared to the other field treatments, including imiquimod, 5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment duration. Alternate illumination methods have also been investigated, including daylight as a light source. Pretreating the affected area may enhance photosensitizer absorption leading to better therapeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ transplant recipients.
Conclusion: This review provides a thorough display of the field of PDT on cancerized skin, which will facilitate physicians in applying PDT more efficiently and intuitively.
References
Dolmans, D.E.; Fukumura, D.; Jain, R.K. Photodynamic therapy for cancer. Nat Rev Cancer 2003, 3, 380-387, doi:10.1038/nrc1071.
Celli, J.P.; Spring, B.Q.; Rizvi, I.; Evans, C.L.; Samkoe, K.S.; Verma, S.; Pogue, B.W.; Hasan, T. Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chemical Reviews 2010, 110, 2795-2838, doi:10.1021/cr900300p.
Morton, C.A.; Szeimies, R.-M.; Basset-Séguin, N.; Calzavara-Pinton, P.G.; Gilaberte, Y.; Hædersdal, M.; Hofbauer, G.F.L.; Hunger, R.E.; Karrer, S.; Piaserico, S.; et al. European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 2: emerging indications – field cancerization, photorejuvenation and inflammatory/infective dermatoses. Journal of the European Academy of Dermatology and Venereology 2020, 34, 17-29, doi:https://doi.org/10.1111/jdv.16044.
Barbaric, J.; Abbott, R.; Posadzki, P.; Car, M.; Gunn, L.H.; Layton, A.M.; Majeed, A.; Car, J. Light therapies for acne: abridged Cochrane systematic review including GRADE assessments. Br J Dermatol 2018, 178, 61-75, doi:10.1111/bjd.15495.
Diepgen, T.L.; Mahler, V. The epidemiology of skin cancer. British Journal of Dermatology 2002, 146, 1-6.
Guorgis, G.; Anderson, C.D.; Lyth, J.; Falk, M. Actinic keratosis diagnosis and increased risk of developing skin cancer: a 10-year cohort study of 17,651 patients in Sweden. Acta Dermato-Venereologica 2020, 100, 1-6.
Slaughter, D.P.; Southwick, H.W.; Smejkal, W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953, 6, 963-968, doi:10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q.
Willenbrink, T.J.; Ruiz, E.S.; Cornejo, C.M.; Schmults, C.D.; Arron, S.T.; Jambusaria-Pahlajani, A. Field cancerization: Definition, epidemiology, risk factors, and outcomes. Journal of the American Academy of Dermatology 2020, 83, 709-717.
Braathen, L.; Morton, C.; Basset‐Seguin, N.; Bissonnette, R.; Gerritsen, M.; Gilaberte, Y.; Calzavara‐Pinton, P.; Sidoroff, A.; Wulf, H.; Szeimies, R.M. Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology. Journal of the European Academy of Dermatology and Venereology 2012, 26, 1063-1066.
Schulten, R.; Novak, B.; Schmitz, B.; Lübbert, H. Comparison of the uptake of 5-aminolevulinic acid and its methyl ester in keratinocytes and skin. Naunyn-Schmiedeberg's Archives of Pharmacology 2012, 385, 969-979, doi:10.1007/s00210-012-0777-4.
Lee, C.-N.; Hsu, R.; Chen, H.; Wong, T.-W. Daylight photodynamic therapy: An update. Molecules 2020, 25, 5195.
Callen, J.P.; Bickers, D.R.; Moy, R.L. Actinic keratoses. Journal of the American Academy of Dermatology 1997, 36, 650-653.
Kim, I.; He, Y.-Y. Ultraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and inflammation. Genes & Diseases 2014, 1, 188-198, doi:https://doi.org/10.1016/j.gendis.2014.08.005.
Rosso, J.D.; Armstrong, A.W.; Berman, B.; Bhatia, N.; Cockerell, C.; Goldenberg, G.; Kirby, J.; Lebwohl, M.; Stein Gold, L.; Marson, J.W.; et al. Advances and Considerations in the Management of Actinic Keratosis: An Expert Consensus Panel Report. J Drugs Dermatol 2021, 20, 888-893, doi:10.36849/jdd.6078.
Szeimies, R.M.; 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, 150-159, doi:10.1111/j.1365-2133.2012.10887.x.
Dirschka, T.; Radny, P.; Dominicus, R.; Mensing, H.; Brüning, H.; Jenne, L.; Karl, L.; Sebastian, M.; Oster‐Schmidt, C.; Klövekorn, W.; et al. Long‐term (6 and 12 months) follow‐up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF‐200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. British Journal of Dermatology 2013, 168, 825-836, doi:10.1111/bjd.12158.
Serra‐Guillén, C.; Nagore, E.; Bancalari, E.; Kindem, S.; Sanmartín, O.; Llombart, B.; Requena, C.; Serra‐Guillén, I.; Calomarde, L.; Diago, A.; et al. A randomized intraindividual comparative study of methyl‐5‐aminolaevulinate vs. 5‐aminolaevulinic acid nanoemulsion (BF‐200 ALA) in photodynamic therapy for actinic keratosis of the face and scalp. British Journal of Dermatology 2018, 179, 1410-1411, doi:10.1111/bjd.17014.
Neittaanmäki‐Perttu, N.; Karppinen, T.T.; Grönroos, M.; Tani, T.T.; 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. British Journal of Dermatology 2014, 171, 1172-1180, doi:10.1111/bjd.13326.
Dirschka, T.; Ekanayake-Bohlig, S.; Dominicus, R.; Aschoff, R.; Herrera-Ceballos, E.; Botella-Estrada, R.; Hunfeld, A.; Kremser, M.; Schmitz, B.; Lübbert, H.; et al. A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis. Journal of the European Academy of Dermatology and Venereology 2019, 33, 288-297, doi:https://doi.org/10.1111/jdv.15185.
Reinhold, U.; Dirschka, T.; Ostendorf, R.; Aschoff, R.; Berking, C.; Philipp-Dormston, W.G.; Hahn, S.; Lau, K.; Jäger, A.; Schmitz, B.; et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp. Br J Dermatol 2016, 175, 696-705, doi:10.1111/bjd.14498.
Räsänen, J.E.; Neittaanmäki, N.; Ylitalo, L.; Hagman, J.; Rissanen, P.; Ylianttila, L.; Salmivuori, M.; Snellman, E.; Grönroos, M. 5‐aminolaevulinic acid nanoemulsion is more effective than methyl‐5‐aminolaevulinate in daylight photodynamic therapy for actinic keratosis: a nonsponsored randomized double‐blind multicentre trial. British Journal of Dermatology 2019, 181, 265-274, doi:10.1111/bjd.17311.
Moloney, F.J.; Collins, P. Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol 2007, 157, 87-91, doi:10.1111/j.1365-2133.2007.07946.x.
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, 171-175, doi:10.1111/j.1365-2133.2009.09492.x.
Kleinpenning, M.M.; van de Kerkhof, P.C.; Gerritsen, R.M. The clinical efficacy of topical methyl-aminolevulinate photodynamic therapy in moderate to severe actinic keratoses of the face and scalp. J Dermatolog Treat 2010, 21, 252-257, doi:10.3109/09546630903271555.
Arisi, M.; Zane, C.; Polonioli, M.; Tomasi, C.; Moggio, E.; Cozzi, C.; Soglia, S.; Caravello, S.; Calzavara-Pinton, I.; Venturini, M.; et al. Effects of MAL-PDT, ingenol mebutate and diclofenac plus hyaluronate gel monitored by high-frequency ultrasound and digital dermoscopy in actinic keratosis - a randomized trial. J Eur Acad Dermatol Venereol 2020, 34, 1225-1232, doi:10.1111/jdv.16123.
Sotiriou, E.; Apalla, Z.; Vrani, F.; Lallas, A.; Chovarda, E.; Ioannides, D. Photodynamic therapy vs. imiquimod 5% cream as skin cancer preventive strategies in patients with field changes: a randomized intraindividual comparison study. J Eur Acad Dermatol Venereol 2015, 29, 325-329, doi:10.1111/jdv.12538.
Jansen, M.H.E.; Kessels, J.; Nelemans, P.J.; Kouloubis, N.; Arits, A.; van Pelt, H.P.A.; Quaedvlieg, P.J.F.; Essers, B.A.B.; Steijlen, P.M.; Kelleners-Smeets, N.W.J.; et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019, 380, 935-946, doi:10.1056/NEJMoa1811850.
Karrer, S.; Aschoff, R.A.G.; Dominicus, R.; Krähn-Senftleben, G.; Gauglitz, G.G.; Zarzour, A.; Kerrouche, N.; Chavda, R.; Szeimies, R.M. Methyl aminolevulinate daylight photodynamic therapy applied at home for non-hyperkeratotic actinic keratosis of the face or scalp: an open, interventional study conducted in Germany. J Eur Acad Dermatol Venereol 2019, 33, 661-666, doi:10.1111/jdv.15422.
Assikar, S.; Labrunie, A.; Kerob, D.; Couraud, A.; Bédane, C. Daylight photodynamic therapy with methyl aminolevulinate cream is as effective as conventional photodynamic therapy with blue light in the treatment of actinic keratosis: a controlled randomized intra-individual study. J Eur Acad Dermatol Venereol 2020, 34, 1730-1735, doi:10.1111/jdv.16208.
Sotiriou, E.; Apalla, Z.; Vrani, F.; Lazaridou, E.; Vakirlis, E.; Lallas, A.; Ioannides, D. Daylight photodynamic therapy vs. Conventional photodynamic therapy as skin cancer preventive treatment in patients with face and scalp cancerization: an intra-individual comparison study. J Eur Acad Dermatol Venereol 2017, 31, 1303-1307, doi:10.1111/jdv.14177.
Lacour, J.P.; 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. J Eur Acad Dermatol Venereol 2015, 29, 2342-2348, doi:10.1111/jdv.13228.
Genovese, G.; Fai, D.; Fai, C.; Mavilia, L.; Mercuri, S.R. Daylight methyl-aminolevulinate photodynamic therapy versus ingenol mebutate for the treatment of actinic keratoses: an intraindividual comparative analysis. Dermatol Ther 2016, 29, 191-196, doi:10.1111/dth.12334.
Wiegell, S.R.; Fabricius, S.; Gniadecka, M.; Stender, I.M.; Berne, B.; Kroon, S.; Andersen, B.L.; Mørk, C.; Sandberg, C.; Ibler, K.S.; 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, 1327-1332, doi:10.1111/j.1365-2133.2012.10833.x.
Ulrich, M.; Reinhold, U.; Dominicus, R.; Aschoff, R.; Szeimies, R.M.; Dirschka, T. Red light photodynamic therapy with BF-200 ALA showed superior efficacy in the treatment of actinic keratosis on the extremities, trunk, and neck in a vehicle-controlled phase III study. J Am Acad Dermatol 2021, 85, 1510-1519, doi:10.1016/j.jaad.2021.03.031.
Salido-Vallejo, R.; Jiménez-Nájar, F.; Garnacho-Sucedo, G.; Vélez, A. Combined daylight and conventional photodynamic therapy with 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) for actinic keratosis of the face and scalp: a new and efficient approach. Arch Dermatol Res 2020, 312, 675-680, doi:10.1007/s00403-019-02028-2.
Gracia-Cazaña, T.; Malinis, A.J.G.; Almagro-Sánchez, M.; Linares, D.P.; Gilaberte, Y. Sequential daylight photodynamic therapy and ingenol mebutate versus 2 sessions of daylight photodynamic therapy for the treatment of actinic keratosis: An observational, prospective, comparative study. Photodiagnosis Photodyn Ther 2019, 27, 34-38, doi:10.1016/j.pdpdt.2019.05.030.
Petukhova, T.A.; Hassoun, L.A.; Foolad, N.; Barath, M.; Sivamani, R.K. Effect of Expedited Microneedle-Assisted Photodynamic Therapy for Field Treatment of Actinic Keratoses: A Randomized Clinical Trial. JAMA Dermatol 2017, 153, 637-643, doi:10.1001/jamadermatol.2017.0849.
Torezan, L.; Chaves, Y.; Niwa, A.; Sanches, J.A., Jr.; Festa-Neto, C.; Szeimies, R.M. A pilot split-face study comparing conventional methyl aminolevulinate-photodynamic therapy (PDT) with microneedling-assisted PDT on actinically damaged skin. Dermatol Surg 2013, 39, 1197-1201, doi:10.1111/dsu.12233.
Torezan, L.; Grinblat, B.; Haedersdal, M.; Valente, N.; Festa-Neto, C.; Szeimies, R.M. A randomized split-scalp study comparing calcipotriol-assisted methyl aminolaevulinate photodynamic therapy (MAL-PDT) with conventional MAL-PDT for the treatment of actinic keratosis. Br J Dermatol 2018, 179, 829-835, doi:10.1111/bjd.16473.
Bullock, T.A.; Negrey, J.; Hu, B.; Warren, C.B.; Hasan, T.; Maytin, E.V. Significant improvement of facial actinic keratoses after blue light photodynamic therapy with oral vitamin D pretreatment: An interventional cohort-controlled trial. J Am Acad Dermatol 2022, 87, 80-86, doi:10.1016/j.jaad.2022.02.067.
Maytin, E.V.; Anand, S.; Riha, M.; Lohser, S.; Tellez, A.; Ishak, R.; Karpinski, L.; Sot, J.; Hu, B.; Denisyuk, A.; et al. 5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial. Clin Cancer Res 2018, 24, 3026-3035, doi:10.1158/1078-0432.Ccr-17-2020.
Pires, M.T.F.; Pereira, A.D.; Durães, S.M.B.; Issa, M.C.A.; Pires, M. Laser-assisted MAL-PDT associated with acoustic pressure wave ultrasound with short incubation time for field cancerization treatment: A left-right comparison. Photodiagnosis Photodyn Ther 2019, 28, 216-220, doi:10.1016/j.pdpdt.2019.08.034.
Vrani, F.; Sotiriou, E.; Lazaridou, E.; Vakirlis, E.; Sideris, N.; Kirmanidou, E.; Apalla, Z.; Lallas, A.; Ioannides, D. Short incubation fractional CO(2) laser-assisted photodynamic therapy vs. conventional photodynamic therapy in field-cancerized skin: 12-month follow-up results of a randomized intraindividual comparison study. J Eur Acad Dermatol Venereol 2019, 33, 79-83, doi:10.1111/jdv.15109.
Togsverd-Bo, K.; Haak, C.S.; Thaysen-Petersen, D.; Wulf, H.C.; Anderson, R.R.; Hædersdal, M. Intensified photodynamic therapy of actinic keratoses with fractional CO2 laser: a randomized clinical trial. Br J Dermatol 2012, 166, 1262-1269, doi:10.1111/j.1365-2133.2012.10893.x.
Bento, C.O.; Pantaleão, L.; de Souza, M.B.; Vilar, E.A.G.; Luiz, R.R.; Filho, P.J.S.; Gismondi, R.; Issa, M.C.A. Comparison of clinical and histologic findings in daylight photodynamic therapy for skin field cancerization: A randomized controlled four-arm study on physical methods-assisted delivery of methyl aminolevulinate. Photodiagnosis Photodyn Ther 2021, 35, 102404, doi:10.1016/j.pdpdt.2021.102404.
Togsverd-Bo, K.; Lei, U.; Erlendsson, A.M.; Taudorf, E.H.; Philipsen, P.A.; Wulf, H.C.; Skov, L.; Hædersdal, M. Combination of ablative fractional laser and daylight-mediated photodynamic therapy for actinic keratosis in organ transplant recipients - a randomized controlled trial. Br J Dermatol 2015, 172, 467-474, doi:10.1111/bjd.13222.
Togsverd-Bo, K.; Omland, S.H.; Wulf, H.C.; Sørensen, S.S.; Haedersdal, M. Primary prevention of skin dysplasia in renal transplant recipients with photodynamic therapy: a randomized controlled trial. Am J Transplant 2015, 15, 2986-2990, doi:10.1111/ajt.13358.
Piacquadio, D.; Houlihan, A.; Ferdon, M.B.; Berg, J.E.; Marcus, S.L. A Randomized Trial of Broad Area ALA-PDT for Field Cancerization Mitigation in High-Risk Patients. J Drugs Dermatol 2020, 19, 452-458.
Published
Issue
Section
License
Copyright (c) 2023 Aikaterini Bakirtzi, Ilias Papadimitriou, Efstratios Vakirlis, Aimilios Lallas, Eleni Sotiriou
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Dermatology Practical & Conceptual applies a Creative Commons Attribution License (CCAL) to all works we publish (http://creativecommons.org/licenses/by-nc/4.0/). Authors retain the copyright for their published work.
How to Cite
Share
