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Systematic review of randomized controlled trials of topicals for actinic keratosis field therapy

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Abstract

Cutaneous field cancerization in dermatology describes the anatomic region of photodamaged skin with actinic keratoses (AKs) or cutaneous squamous cell carcinoma (cSCC) that is surrounded by cellular atypia, forming a dysplastic field. The concept of field cancerization is especially relevant in dermatology, as actinic keratoses and the surrounding dysplastic region can progress to carcinomas, necessitating the treatment of the field. Recent research has focused on field-directed therapy using topical agents. This study aims to systematically review randomized controlled trials on topical treatments for actinic keratosis field cancerization, following the PRISMA guidelines. Clinical recommendations were based on the Oxford Centre for Evidence-Based Medicine. We identified 20 original randomized controlled trials for topical cutaneous field therapy. 0.5% 5-Fluorouracil/salicylic acid and 0.5% 5-fluorouracil received a clinical recommendation grade of A, while diclofenac sodium received a clinical recommendation grade of B. Calcipotriol/5-fluorouracil, Imiquimod, sunscreen combination therapies, and tirbanibulin received a recommendation grade of C. This review provides a framework for clinicians when considering topical treatments for patients with field cancerization.

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The data that support the evidence presented in this article is accessible from public databases including PubMed, Embase, and Cochrane.

References

  1. Willenbrink TJ et al (2020) Field cancerization: definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol 83(3):709–717

    Article  CAS  PubMed  Google Scholar 

  2. Huang A et al (2019) Updates on treatment approaches for cutaneous field cancerization. Curr Dermatol Rep 8(3):122–132

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lanoue J, Chen C, Goldenberg G (2016) Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies. Cutis 97(6):415–420

    PubMed  Google Scholar 

  4. Christensen SR (2018) Recent advances in field cancerization and management of multiple cutaneous squamous cell carcinomas. F1000Res. https://doi.org/10.12688/f1000research.12837.1

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rogers HW et al (2015) Incidence estimate of nonmelanoma skin cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol 151(10):1081–1086

    Article  PubMed  Google Scholar 

  6. Figueras Nart I et al (2018) Defining the actinic keratosis field: a literature review and discussion. J Eur Acad Dermatol Venereol 32(4):544–563

    Article  CAS  PubMed  Google Scholar 

  7. Torezan LA, Festa-Neto C (2013) Cutaneous field cancerization: clinical, histopathological and therapeutic aspects. An Bras Dermatol 88(5):775–786

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cheraghlou S, Feng H, Cohen JM (2020) Trends in the access and cost of photodynamic therapy among Medicare beneficiaries in the United States, 2012–2017. JAMA Dermatol 156(9):1021–1022

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jansen MHE et al (2020) A trial-based cost-effectiveness analysis of topical 5-fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the head and neck area performed in the Netherlands. Br J Dermatol 183(4):738–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nelson CG (2011) Diclofenac gel in the treatment of actinic keratoses. Ther Clin Risk Manag 7:207–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Korman N et al (2005) Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 141(4):467–473

    Article  CAS  PubMed  Google Scholar 

  12. Heron CE, Feldman SR (2021) Ingenol mebutate and the treatment of actinic keratosis. J Drugs Dermatol 20(1):102–104

    Article  PubMed  Google Scholar 

  13. Rosso JD et al (2021) Advances and considerations in the management of actinic keratosis: an expert consensus panel report. J Drugs Dermatol 20(8):888–893

    Article  PubMed  Google Scholar 

  14. Jansen MHE et al (2019) Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med 380(10):935–946

    Article  CAS  PubMed  Google Scholar 

  15. Oxford Centre for Evidence-Based Medicine: levels of evidence (March 2009). Centre for Evidence Based Medicine 2009. cited 7 Aug 2023.

  16. Ghafouri-Fard S et al (2021) 5-Fluorouracil: a narrative review on the role of regulatory mechanisms in driving resistance to this chemotherapeutic agent. Front Oncol 11:658636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stockfleth E et al (2017) Efficacy and safety of 5-fluorouracil 0.5%/salicylic acid 10% in the field-directed treatment of actinic keratosis: a phase III, randomized, double-blind, vehicle-controlled trial. Dermatol Ther (Heidelb) 7(1):81–96

    Article  PubMed  Google Scholar 

  18. Stockfleth E et al (2011) Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol 165(5):1101–1108

    Article  CAS  PubMed  Google Scholar 

  19. Jorizzo J et al (2002) Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis. Cutis 70(6):335–339

    PubMed  Google Scholar 

  20. Loven K et al (2002) Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther 24(6):990–1000

    Article  CAS  PubMed  Google Scholar 

  21. Wolf JE Jr et al (2001) Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40(11):709–713

    Article  CAS  PubMed  Google Scholar 

  22. Mazzella C et al (2018) Management of clinical and subclinical actinic keratoses with histological and immunohistochemical assessments by confocal microscopy. Dermatol Ther 31(5):e12672

    Article  PubMed  Google Scholar 

  23. Ulrich M et al (2010) Reflectance confocal microscopy for noninvasive monitoring of therapy and detection of subclinical actinic keratoses. Dermatology 220(1):15–24

    Article  CAS  PubMed  Google Scholar 

  24. Rivers JK et al (2002) Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146(1):94–100

    Article  CAS  PubMed  Google Scholar 

  25. Kim GK (2010) The rationale behind topical vitamin d analogs in the treatment of psoriasis: where does topical calcitriol fit in? J Clin Aesthet Dermatol 3(8):46–53

    PubMed  PubMed Central  Google Scholar 

  26. Cunningham TJ et al (2017) Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 127(1):106–116

    Article  PubMed  Google Scholar 

  27. Bubna AK (2015) Imiquimod—its role in the treatment of cutaneous malignancies. Indian J Pharmacol 47(4):354–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ulrich C et al (2007) Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 157(Suppl 2):25–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen K et al (2003) Short-course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Australas J Dermatol 44(4):250–255

    Article  PubMed  Google Scholar 

  30. Swanson N et al (2010) Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 62(4):582–590

    Article  CAS  PubMed  Google Scholar 

  31. Jorizzo J et al (2007) Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol 57(2):265–268

    Article  PubMed  Google Scholar 

  32. Alomar A, Bichel J, McRae S (2007) Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 157(1):133–141

    Article  CAS  PubMed  Google Scholar 

  33. Szeimies RM et al (2004) Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51(4):547–555

    Article  PubMed  Google Scholar 

  34. Gebauer K, Shumack S, Cowen PS (2009) Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial. Br J Dermatol 161(4):897–903

    Article  CAS  PubMed  Google Scholar 

  35. Carducci M et al (2015) Comparative effects of sunscreens alone vs sunscreens plus DNA repair enzymes in patients with actinic keratosis: clinical and molecular findings from a 6-month, randomized. Clinical Study J Drugs Dermatol 14(9):986–990

    CAS  PubMed  Google Scholar 

  36. Bobyr I et al (2019) Fluorescent photodiagnostic evaluation of field cancerization treated with a medical device containing piroxicam 08% and sunscreen SPF 50+ for actinic keratosis. Photodermatol Photoimmunol Photomed 35(4):277–279

    Article  PubMed  Google Scholar 

  37. Alvares BA et al (2022) Efficacy of sunscreen with photolyase or regular sunscreen associated with topical antioxidants in treating advanced photodamage and cutaneous field cancerization: a randomized clinical trial. An Bras Dermatol 97(2):157–165

    Article  PubMed  PubMed Central  Google Scholar 

  38. Luze H et al (2020) DNA repair enzymes in sunscreens and their impact on photoageing-A systematic review. Photodermatol Photoimmunol Photomed 36(6):424–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berman B, Grada A, Berman DK (2022) Profile of tirbanibulin for the treatment of actinic keratosis. J Clin Aesthet Dermatol 15(10 Suppl 1):S3–S10

    PubMed  PubMed Central  Google Scholar 

  40. Blauvelt A et al (2021) Phase 3 trials of tirbanibulin ointment for actinic keratosis. N Engl J Med 384(6):512–520

    Article  CAS  PubMed  Google Scholar 

  41. Kishi P, Price CJ (2018) Life-threatening reaction with topical 5-fluorouracil. Drug Saf Case Rep 5(1):4

    Article  PubMed  PubMed Central  Google Scholar 

  42. Johnson MR et al (1999) Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 5(8):2006–2011

    CAS  PubMed  Google Scholar 

  43. Papanastasopoulos P, Stebbing J (2014) Molecular basis of 5-fluorouracil-related toxicity: lessons from clinical practice. Anticancer Res 34(4):1531–1535

    CAS  PubMed  Google Scholar 

  44. Suh SA-O et al (2020) The banned sunscreen ingredients and their impact on human health: a systematic review. Int J Dermatol 59:1365–4632

    Article  Google Scholar 

  45. Ortonne JP et al (2010) Effectiveness of cross polarized light and fluorescence diagnosis for detection of sub-clinical and clinical actinic keratosis during imiquimod treatment. Exp Dermatol 19(7):641–647

    Article  CAS  PubMed  Google Scholar 

  46. Baker C et al (2022) Method of Assessing Skin Cancerization and Keratoses(TM) (MASCK): development and photographic validation in multiple anatomical sites of a novel assessment tool intended for clinical evaluation of patients with extensive skin field cancerization. Clin Exp Dermatol 47(6):1144–1153

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

PP performed the literature search and wrote the main manuscript. PP and JW reviewed the studies independently. JW, DB, JM, and EA helped to review the manuscript. JJ helped to develop the concept and edit/review the final manuscript. All authors reviewed and approved the final manuscript.

Funding

No funding has been received for this article. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Dermatology Service, Veterans Affairs New York Harbor Healthcare System-Brooklyn Campus, Brooklyn, NY, USA

    Paras Patel, Jennifer Wang, David Bitterman, Jessica Mineroff, Evan Austin & Jared Jagdeo

  2. Rowan University School of Osteopathic Medicine, Stratford, NJ, USA

    Paras Patel

  3. Department of Dermatology, State University of New York, Downstate Health Sciences University, 450 Clarkson Avenue, 8 Floor, Brooklyn, NY, 11203, USA

    Jennifer Wang, Jessica Mineroff, Evan Austin & Jared Jagdeo

  4. New York Medical College, Valhalla, NY, USA

    David Bitterman

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  1. Paras Patel
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PP performed the literature search and wrote the main manuscript. PP and JW reviewed the studies independently. JW, DB, JM, and EA helped to review the manuscript. JJ helped to develop the concept and edit/review the final manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Jared Jagdeo.

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Patel, P., Wang, J., Bitterman, D. et al. Systematic review of randomized controlled trials of topicals for actinic keratosis field therapy. Arch Dermatol Res 316, 108 (2024). https://doi.org/10.1007/s00403-024-02839-y

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  • DOI: https://doi.org/10.1007/s00403-024-02839-y

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