{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:55:12Z","timestamp":1792716912696,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Actinic keratoses are common keratinocytic precursor lesions arising within chronically ultraviolet-damaged skin and are associated with an increased risk of progression to cutaneous squamous cell carcinoma. The concept of field cancerization has shifted therapeutic strategies from the treatment of isolated visible lesions toward broader field-directed approaches targeting both clinical and subclinical disease. Methods: This narrative review summarizes the rationale, mechanisms of action, efficacy profile, tolerability, and practical limitations of currently available field-directed therapies for actinic keratosis, including 5-fluorouracil, imiquimod, diclofenac, photodynamic therapy, and tirbanibulin. Based on their distinct biological targets, we propose a mechanism-based framework for sequential treatment strategies. Results: Available therapies act through partially non-overlapping mechanisms, including cytotoxic activity, immune activation, cyclooxygenase-2 inhibition, photodynamic oxidative damage, and tubulin\/Src pathway inhibition. These complementary effects provide a biological rationale for sequential regimens aimed at addressing the heterogeneity of field cancerization. However, direct clinical evidence supporting specific treatment sequences remains limited, and proposed regimens should be interpreted as hypothesis-generating rather than as validated therapeutic protocols. Conclusions: Mechanism-based sequential field therapy may represent a rational strategy to optimize long-term control of actinic keratosis and field cancerization. Prospective comparative studies are needed to define optimal sequences, treatment intervals, patient selection criteria, and clinically meaningful endpoints, including sustained field clearance, recurrence reduction, tolerability, adherence, and prevention of progression to invasive cutaneous squamous cell carcinoma.<\/jats:p>","DOI":"10.3390\/jcm15124553","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"4553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sequential Field Therapy in Actinic Keratosis: A Mechanism-Based Rationale for Complementary Treatment Strategies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1640-6609","authenticated-orcid":false,"given":"Giulio","family":"Gualdi","sequence":"first","affiliation":[{"name":"University Hospital, Ospedale Maggiore di Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Soligon","sequence":"additional","affiliation":[{"name":"University Hospital, Ospedale Maggiore di Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-3848","authenticated-orcid":false,"given":"Patrick","family":"Silvetti","sequence":"additional","affiliation":[{"name":"University Hospital, Ospedale Maggiore di Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4466-443X","authenticated-orcid":false,"given":"Leonardo","family":"Balestra","sequence":"additional","affiliation":[{"name":"University Hospital, Ospedale Maggiore di Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9700-5542","authenticated-orcid":false,"given":"Davide","family":"Bertolla","sequence":"additional","affiliation":[{"name":"University Hospital, Ospedale Maggiore di Parma, 43126 Parma, Italy"},{"name":"Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Fania","sequence":"additional","affiliation":[{"name":"Skin Cancer Center, Istituto Dermopatico dell\u2019Immacolata-IRCCS, 00167 Rome, Italy"},{"name":"Department of Life Science, Health, and Health Professions, Link University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8388-9268","authenticated-orcid":false,"given":"Francesco","family":"Ricci","sequence":"additional","affiliation":[{"name":"Skin Cancer Center, Istituto Dermopatico dell\u2019Immacolata-IRCCS, 00167 Rome, Italy"},{"name":"Department of Life Science, Health, and Health Professions, Link University of Rome, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-2581","authenticated-orcid":false,"given":"Mario","family":"Puviani","sequence":"additional","affiliation":[{"name":"Dermatology Clinic, Sassuolo Hospital, 41049 Sassuolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Sbano","sequence":"additional","affiliation":[{"name":"Dermatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Paradisi","sequence":"additional","affiliation":[{"name":"Dermatology Unit, Department of Medical, Surgical, Abdominal and Endocrine-Metabolic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/bjd\/ljad371","article-title":"Global epidemiology of actinic keratosis in the general population: A systematic review and meta-analysis","volume":"190","author":"George","year":"2024","journal-title":"Br. J. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S0140-6736(88)91658-3","article-title":"Malignant transformation of solar keratoses to squamous cell carcinoma","volume":"331","author":"Marks","year":"1988","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1001\/archderm.1991.01680060103013","article-title":"Malignant potential of actinic keratoses and the controversy over treatment. 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