The Role of Field Cancerization in Selecting Therapies for Actinic Keratosis: An Expert Consensus Panel
Main Article Content
Keywords
actinic keratosis, actinic keratoses, AK, field cancerization, field therapy, skin cancer
Abstract
Background: Actinic keratosis is a very common disease that affects over 40 million people in the United States. In addition to the clinically visible lesion, patients may present with surrounding field cancerization based on their history of ultraviolet exposure. While lesion-directed therapy such as cryosurgery can effectively treat individual actinic keratoses it does not treat subclinical lesions or field cancerization.
Objective: To create consensus recommendations on the role of field cancerization in selecting appropriate therapy for actinic keratoses.
Methods: A comprehensive literature search of PubMed, Google Scholar, and Embase was conducted using the keywords “actinic keratos*,” “treatment,” and “field cancerization” for English-language original research articles without date restrictions. Articles were included that either discussed the role of FC in treating AKs or compared various AK field therapies. The relevant articles were then distributed to a panel of nine dermatologists with significant expertise in managing AKs. Each panelist reviewed the articles and assigned them a level of evidence based on Strength of Recommendation Taxonomy (SORT) criteria. The panel then convened on to discuss the studies and develop consensus statements on the role of FC in selecting AK therapy. The panel utilized a modified Delphi process to approve the adoption of each statement and gave each one a strength of recommendation based on SORT criteria.
Results: The initial literature search produced 243 articles that met search criteria. After a thorough screening of these articles for relevance to the research question, 21 articles were chosen to be reviewed by the panel and assigned a level of evidence. Of the 21 articles that were reviewed, the panel assigned level 1 evidence to three articles, level 2 evidence to six articles, and level 3 evidence to twelve articles. The panel created seven consensus statements related to AK management and FC. All seven statements received a unanimous (9/9) vote for adoption. Each of the statements was given a strength of recommendation according to sort criteria
Conclusion: Field cancerization due to chronic ultraviolet exposure leads to subclinical AK lesions in addition to lesions that are clinically apparent. In order to address these lesions, field therapy is an important component of an adequate regimen and can be used in conjunction with lesion-directed therapy for optimal results.
References
2. George CD, Lee T, Hollestein LM, Asgari MM, Nijsten T. Global epidemiology of actinic keratosis in the general population: a systematic review and meta-analysis. Br J Dermatol. 2024;190(4):465-476. doi:10.1093/bjd/ljad371
3. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957-966. doi:10.1016/j.jaad.2012.11.037
4. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237-247. doi:10.1016/j.jaad.2017.08.059
5. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523-2530. doi:10.1002/cncr.24284
6. Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. doi:10.1111/bjd.12420
7. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42(1 Pt 2):23-24. doi:10.1067/mjd.2000.103339
8. Marks R, Foley P, Goodman G, Hage BH, Selwood TS. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol. 1986;115(6):649-655. doi:10.1111/j.1365-2133.1986.tb06644.x
9. Hashim PW, Chen T, Rigel D, Bhatia N, Kircik LH. Actinic Keratosis: Current Therapies and Insights Into New Treatments. J Drugs Dermatol. 2019;18(5):s161-166.
10. Quaedvlieg PJ, Tirsi E, Thissen MR, Krekels GA. Actinic keratosis: how to differentiate the good from the bad ones?. Eur J Dermatol. 2006;16(4):335-339.
11. Dianzani C, Conforti C, Giuffrida R, et al. Current therapies for actinic keratosis. Int J Dermatol. 2020;59(6):677-684. doi:10.1111/ijd.14767
12. Willenbrink TJ, Ruiz ES, Cornejo CM, Schmults CD, Arron ST, Jambusaria-Pahlajani A. Field cancerization: Definition, epidemiology, risk factors, and outcomes. J Am Acad Dermatol. 2020;83(3):709-717. doi:10.1016/j.jaad.2020.03.126
13. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6(5):963-968. doi:10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q
14. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res. 2003;63(8):1727-1730.
15. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):548-556.
16. Hsu C-C, Sandford BA. The Delphi technique: making sense of consensus. Practical assessment, research & evaluation 2007;12:1-8.
17. Berman B, Ceilley R, Cockerell C, et al. (2019). Appropriate Use Criteria for the Integration of Diagnostic and Prognostic Gene Expression Profile Assays into the Management of Cutaneous Malignant Melanoma: An Expert Panel Consensus-Based Modified Delphi Process Assessment. SKIN The Journal of Cutaneous Medicine, 3(5), 291–306. doi:10.25251/skin.3.5.1
18. Thiboutot DM, Dréno B, Abanmi A, et al. Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018;78(2 Suppl 1):S1-S23.e1. doi:10.1016/j.jaad.2017.09.078
19. Richard MA, Barnetche T, Rouzaud M, et al. Evidence-based recommendations on the role of dermatologists in the diagnosis and management of psoriatic arthritis: systematic review and expert opinion. J Eur Acad Dermatol Venereol. 2014;28 Suppl 5:3-12. doi:10.1111/jdv.12560
20. Zakria, D., Brownstone, N., Berman, B., Ceilley, R., Goldenberg, G., Lebwohl, M., Litchman, G., & Siegel, D. (2023). Incorporating Prognostic Gene Expression Profile Assays into the Management of Cutaneous Melanoma: An Expert Consensus Panel Report. SKIN The Journal of Cutaneous Medicine, 7(1), 556–569. https://doi.org/10.25251/skin.7.1.1
21. Blauvelt A, Kempers S, Lain E, et al. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. N Engl J Med. 2021;384(6):512-520. doi:10.1056/NEJMoa2024040
22. Gupta AK, Paquet M. Network meta-analysis of the outcome 'participant complete clearance' in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169(2):250-259. doi:10.1111/bjd.12343
23. Piacquadio D, Houlihan A, Ferdon MB, Berg JE, Marcus SL. A Randomized Trial of Broad Area ALA-PDT for Field Cancerization Mitigation in High-Risk Patients. J Drugs Dermatol. 2020;19(5):452-458.
24. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019;380(10):935-946. doi:10.1056/NEJMoa1811850
25. Lampley N 3rd, Rigo R, Schlesinger T, Rossi AM. Field Therapy for Actinic Keratosis: A Structured Review of the Literature on Efficacy, Cost, and Adherence. Dermatol Surg. 2023;49(2):124-129. doi:10.1097/DSS.0000000000003677
26. Micali G, Verzì AE, Barresi S, Dirschka T, Lacarrubba F. Field cancerization in clinically solitary actinic keratosis: A pilot study. Dermatol Ther. 2021;34(1):e14607. doi:10.1111/dth.14607
27. Rajkumar JR, Armstrong AW, Kircik LH. Safety and Tolerability of Topical Agents for Actinic Keratosis: A Systematic Review of Phase 3 Clinical Trials. J Drugs Dermatol. 2021;20(10):s4s4-s14. doi:10.36849/JDD.M1021
28. Schlesinger, T., Kircik, L., Del Rosso, J., Rigel, D., Lebwohl, M., Berman, B., Armstrong, A., Bhatia, N., Patel, V. A., Narayanan, S., Koscielny, V., & Kasujee, I. (2023). Clinician- and Patient-Reported Outcomes with Tirbanibulin 1% Treatment for Actinic Keratosis in Routine Clinical Practice Across the U.S. (PROAK Study). SKIN The Journal of Cutaneous Medicine, 7(3), 771–787. https://doi.org/10.25251/skin.7.3.3
29. Worley B, Harikumar V, Reynolds K, et al. Treatment of actinic keratosis: a systematic review. Arch Dermatol Res. 2023;315(5):1099-1108. doi:10.1007/s00403-022-02490-5
30. Cornejo CM, Jambusaria-Pahlajani A, Willenbrink TJ, Schmults CD, Arron ST, Ruiz ES. Field cancerization: Treatment. J Am Acad Dermatol. 2020;83(3):719-730. doi:10.1016/j.jaad.2020.03.127
31. Dirschka T, Gupta G, Micali G, et al. Real-world approach to actinic keratosis management: practical treatment algorithm for office-based dermatology. J Dermatolog Treat. 2017;28(5):431-442. doi:10.1080/09546634.2016.1254328
32. Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2021;85(4):e209-e233. doi:10.1016/j.jaad.2021.02.082
33. Eisen DB, Dellavalle RP, Frazer-Green L, Schlesinger TE, Shive M, Wu PA. Focused update: Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2022;87(2):373-374.e5. doi:10.1016/j.jaad.2022.04.013
34. Goldenberg G. Treatment considerations in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:12-16. doi:10.1111/jdv.14152
35. Han, H., & Berman, B. (2022). Clinical Management of Actinic Keratosis: Review and Update. SKIN The Journal of Cutaneous Medicine, 6(4), 274–285. https://doi.org/10.25251/skin.6.4.1
36. Figueras Nart I, Cerio R, Dirschka T, et al. Defining the actinic keratosis field: a literature review and discussion. J Eur Acad Dermatol Venereol. 2018;32(4):544-563. doi:10.1111/jdv.14652
37. Pariser DM. Approaches to Field Therapy for Actinic Keratoses: Relating Clinical Trial Results to Real-world Practice-A Commentary. J Clin Aesthet Dermatol. 2022;15(4):40-43.
38. Sinclair R, Baker C, Spelman L, Supranowicz M, MacMahon B. A review of actinic keratosis, skin field cancerisation and the efficacy of topical therapies. Australas J Dermatol. 2021;62(2):119-123. doi:10.1111/ajd.13447
39. Stockfleth E. The importance of treating the field in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:8-11. doi:10.1111/jdv.14092
40. Zakria, D., Armstrong, A., Berman, B., Del Rosso, J., Lebwohl, M., Schlesinger, T., & Rigel, D. (2023). The Importance of Medication Adherence in the Treatment of Actinic Keratosis: An Expert Consensus Panel. SKIN The Journal of Cutaneous Medicine, 7(3), 752–763. https://doi.org/10.25251/skin.7.3.1
41. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol. 1998;37(9):677-681. doi:10.1046/j.1365-4362.1998.00467.x
42. Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. doi:10.1111/bjd.12420
43. Weinstock MA, Thwin SS, Siegel JA, et al. Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial. JAMA Dermatol. 2018;154(2):167-174. doi:10.1001/jamadermatol.2017.3631
44. Neugebauer R, Levandoski KA, Zhu Z, et al. A real-world, community-based cohort study comparing the effectiveness of topical fluorouracil versus topical imiquimod for the treatment of actinic keratosis. J Am Acad Dermatol. 2018;78(4):710-716. doi:10.1016/j.jaad.2017.12.042
45. Pomerantz H, Hogan D, Eilers D, et al. Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. JAMA Dermatol. 2015;151(9):952-960. doi:10.1001/jamadermatol.2015.0502
46. Malvehy J, Alarcon I, Montoya J, Rodríguez-Azeredo R, Puig S. Treatment monitoring of 0.5% 5-fluorouracil and 10% salicylic acid in clinical and subclinical actinic keratoses with the combination of optical coherence tomography and reflectance confocal microscopy. J Eur Acad Dermatol Venereol. 2016;30(2):258-265. doi:10.1111/jdv.13445
47. Ulrich M, Reinhold U, Falqués M, Rodriguez Azeredo R, Stockfleth E. Use of reflectance confocal microscopy to evaluate 5-fluorouracil 0.5%/salicylic acid 10% in the field-directed treatment of subclinical lesions of actinic keratosis: subanalysis of a Phase III, randomized, double-blind, vehicle-controlled trial. J Eur Acad Dermatol Venereol. 2018;32(3):390-396. doi:10.1111/jdv.14611
48. Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results. J Drugs Dermatol. 2014;13(2):154-160.
49. Szeimies RM, Gerritsen MJ, Gupta G, et al. 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. 2004;51(4):547-555. doi:10.1016/j.jaad.2004.02.022
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Creative Commons Attribution (CC BY): lets others distribute and copy the article, to create extracts, abstracts, and other revised versions, adaptations or derivative works of or from an article (such as a translation), to include in a collective work (such as an anthology), to text or data mine the article, even for commercial purposes, as long as they credit the author(s), do not represent the author as endorsing their adaptation of the article, and do not modify the article in such a way as to damage the author's honor or reputation.
Authors retain copyright in their work and license the publisher to publish the content. The publisher is the National Society for Cutaneous Medicine, with production and publishing support provided by OJS, Open Journal Systems,see https://pkp.sfu.
Prior to January 2022, authors transferred copyright to the National Society for Cutaneous Medicine. However, all articles are freely available to anyone in the world. There are no subscription fees, page charges, or article processing charges.