5. Sinclair R, Baker C, Spelman L, Supranowicz M, MacMahon B. A review of actinic keratosis, skin field cancerisation and the efficacy of topical therapies. Australa J Dermatol.
6. Andrade FAG, de Isoldi FC, Ferreira LM. Skin field cancerisation: A systematic review of the literature regarding its treatment. Eur J Cancer Care (Engl) n/a, e13366.
7. Werner RN, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 169, 502–518 (2013).
8. Werner RN, 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. J Eur Acad Dermatol Venereol. 29, 2069–2079 (2015).
9. Dillaha CJ, Jansen GT, Honeycutt WM, Bradford AC. Selective cytotoxic effect of topical 5-fluorouracil. Arch Dermatol. 88, 247–256 (1963).
10. Blauvelt A, et al. Phase 3 trials of tirbanibulin ointment for actinic keratosis. N Engl J Med. 384, 512–520 (2021).
11. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 3, e123–e130 (2009).
12. Dianzani C, et al. Current therapies for actinic keratosis. Int J Dermatol. 59, 677–684 (2020).
13. Wu Y, Tang N, Cai L, Li Q. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: A network metaanalysis. Dermatol. Ther. 32, e12822 (2019).
14. Askew DA, Mickan SM, Soyer HP, Wilkinson D. Effectiveness of 5-fluorouracil treatment for actinic keratosis – a systematic review of randomized controlled trials. Int. J. Dermatol. 48, 453–463 (2009).
15. Stockfleth E, Sibbring GC, Alarcon I. New topical treatment options for actinic keratosis: a systematic review. Acta Derm. Venereol. 96, 17–22 (2016).
16. Dohil MA. Efficacy, safety, and tolerability of 4% 5-fluorouracil cream in a novel patented aqueous cream containing peanut oil once daily compared with 5% 5-fluorouracil cream twice daily: Meeting the challenge in the treatment of actinic keratosis. J Drugs Dermatol. 15, 1218–1224 (2016).
17. Gupta AK, Weiss JS, Jorizzo JL. 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin Ther Lett. 6, 1–4 (2001).
18. Hill Dermaceuticals. Tolak [prescribing information]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2015/022259s000lbl.pdf. Revised September 2015. Accessed January 10th, 2021.
19. Hoover WD, et al. Efficacy of cryosurgery and 5-fluorouracil cream 0.5% combination therapy for the treatment of actinic keratosis. Cutis 94, 255– 259 (2014).
20. Weiss J, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis 70, 22–29 (2002).
21. Jorizzo J, et al. 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, 335–339 (2002).
22. Torres A, et al. Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med. 5, 7 (2007).
23. Lebwohl M, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehiclecontrolled trials. J Am Acad Dermatol. 50, 714–721 (2004).
24. Korman N, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, doubleblind, parallel-group, vehicle-controlled trials. Arch Dermatol. 141, 467–473 (2005).
25. Swanson N, et al. 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, 582–590 (2010).
26. Hanke CW, et al. 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 3-week cycles. J Am Acad Dermatol. 62, 573–581 (2010).
27. Hanke CW, et al. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp via daily dosing with imiquimod 3.75% or 2.5% cream. J. Drugs Dermatol. 10, 165– 170 (2011).
28. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 66, 486–493 (2012).
29. Lebwohl M, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 366, 1010–1019 (2012).
30. Hanke CW, et al. Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp, or approximately 250 cm2 on the chest: A phase 3 randomized controlled trial. J Am Acad Dermatol. 82, 642–650 (2020).
31. Heron CE, Feldman SR. Ingenol mebutate and the treatment of actinic keratosis. J Drugs Dermatol. 20, 102–104 (2021).
32. Denmark’s LEO Pharma initiates Picato phase-out. https://www. thepharmaletter.com/article/denmark-s-leo-pharma-initiates-picato-phaseout.
33. Nelson CG. Diclofenac gel in the treatment of actinic keratoses. Ther Clin Risk Manag. 7, 207–211 (2011).
34. Almirall Hermal GmbH. Solaraze (diclofenac sodium) [prescribing information]. U.S. Food and Drug Administration website. https://www. accessdata.fda.gov/drugsatfda_docs/label/2011/021005s013lbl.pdf. Revised December 2011. Accessed January 10th, 2021.
35. Stockfleth E, Kerl H, Zwingers T, Willers C. 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, 1101–1108 (2011).
36. Stockfleth E, Zwingers T, Willers C. Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses. Eur J Dermatol. 22, 370–374 (2012).
37. Niu, L. et al. Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1’s low clinical toxicity. J Biol Chem. 294, 18099–18108 (2019).
38. Kempers, S. et al. Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results. J Drugs Dermatol. 19, 1093–1100 (2020).
39. Foley P, et al. Adherence to topical therapies in actinic keratosis: A literature review. J Dermatol Treat. 27, 538–545 (2016).
40. Eisen DB, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 0, (2021).
41. Grada A, Feldman SR, Bragazzi NL, Damiani G. Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review. Dermatol Ther. e14833 (2021) doi:10.1111/dth.14833.
42. Ceilley RI. Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders. J Dermatol Treat. 23, 83–89 (2012).
43. Cramer P, Stockfleth E. Actinic keratosis: where do we stand and where is the future going to take us? Expert Opin Emerg Drugs 25, 49–58 (2020).
6. Andrade FAG, de Isoldi FC, Ferreira LM. Skin field cancerisation: A systematic review of the literature regarding its treatment. Eur J Cancer Care (Engl) n/a, e13366.
7. Werner RN, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 169, 502–518 (2013).
8. Werner RN, 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. J Eur Acad Dermatol Venereol. 29, 2069–2079 (2015).
9. Dillaha CJ, Jansen GT, Honeycutt WM, Bradford AC. Selective cytotoxic effect of topical 5-fluorouracil. Arch Dermatol. 88, 247–256 (1963).
10. Blauvelt A, et al. Phase 3 trials of tirbanibulin ointment for actinic keratosis. N Engl J Med. 384, 512–520 (2021).
11. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 3, e123–e130 (2009).
12. Dianzani C, et al. Current therapies for actinic keratosis. Int J Dermatol. 59, 677–684 (2020).
13. Wu Y, Tang N, Cai L, Li Q. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: A network metaanalysis. Dermatol. Ther. 32, e12822 (2019).
14. Askew DA, Mickan SM, Soyer HP, Wilkinson D. Effectiveness of 5-fluorouracil treatment for actinic keratosis – a systematic review of randomized controlled trials. Int. J. Dermatol. 48, 453–463 (2009).
15. Stockfleth E, Sibbring GC, Alarcon I. New topical treatment options for actinic keratosis: a systematic review. Acta Derm. Venereol. 96, 17–22 (2016).
16. Dohil MA. Efficacy, safety, and tolerability of 4% 5-fluorouracil cream in a novel patented aqueous cream containing peanut oil once daily compared with 5% 5-fluorouracil cream twice daily: Meeting the challenge in the treatment of actinic keratosis. J Drugs Dermatol. 15, 1218–1224 (2016).
17. Gupta AK, Weiss JS, Jorizzo JL. 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin Ther Lett. 6, 1–4 (2001).
18. Hill Dermaceuticals. Tolak [prescribing information]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2015/022259s000lbl.pdf. Revised September 2015. Accessed January 10th, 2021.
19. Hoover WD, et al. Efficacy of cryosurgery and 5-fluorouracil cream 0.5% combination therapy for the treatment of actinic keratosis. Cutis 94, 255– 259 (2014).
20. Weiss J, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis 70, 22–29 (2002).
21. Jorizzo J, et al. 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, 335–339 (2002).
22. Torres A, et al. Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med. 5, 7 (2007).
23. Lebwohl M, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehiclecontrolled trials. J Am Acad Dermatol. 50, 714–721 (2004).
24. Korman N, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, doubleblind, parallel-group, vehicle-controlled trials. Arch Dermatol. 141, 467–473 (2005).
25. Swanson N, et al. 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, 582–590 (2010).
26. Hanke CW, et al. 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 3-week cycles. J Am Acad Dermatol. 62, 573–581 (2010).
27. Hanke CW, et al. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp via daily dosing with imiquimod 3.75% or 2.5% cream. J. Drugs Dermatol. 10, 165– 170 (2011).
28. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 66, 486–493 (2012).
29. Lebwohl M, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 366, 1010–1019 (2012).
30. Hanke CW, et al. Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp, or approximately 250 cm2 on the chest: A phase 3 randomized controlled trial. J Am Acad Dermatol. 82, 642–650 (2020).
31. Heron CE, Feldman SR. Ingenol mebutate and the treatment of actinic keratosis. J Drugs Dermatol. 20, 102–104 (2021).
32. Denmark’s LEO Pharma initiates Picato phase-out. https://www. thepharmaletter.com/article/denmark-s-leo-pharma-initiates-picato-phaseout.
33. Nelson CG. Diclofenac gel in the treatment of actinic keratoses. Ther Clin Risk Manag. 7, 207–211 (2011).
34. Almirall Hermal GmbH. Solaraze (diclofenac sodium) [prescribing information]. U.S. Food and Drug Administration website. https://www. accessdata.fda.gov/drugsatfda_docs/label/2011/021005s013lbl.pdf. Revised December 2011. Accessed January 10th, 2021.
35. Stockfleth E, Kerl H, Zwingers T, Willers C. 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, 1101–1108 (2011).
36. Stockfleth E, Zwingers T, Willers C. Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses. Eur J Dermatol. 22, 370–374 (2012).
37. Niu, L. et al. Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1’s low clinical toxicity. J Biol Chem. 294, 18099–18108 (2019).
38. Kempers, S. et al. Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results. J Drugs Dermatol. 19, 1093–1100 (2020).
39. Foley P, et al. Adherence to topical therapies in actinic keratosis: A literature review. J Dermatol Treat. 27, 538–545 (2016).
40. Eisen DB, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 0, (2021).
41. Grada A, Feldman SR, Bragazzi NL, Damiani G. Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review. Dermatol Ther. e14833 (2021) doi:10.1111/dth.14833.
42. Ceilley RI. Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders. J Dermatol Treat. 23, 83–89 (2012).
43. Cramer P, Stockfleth E. Actinic keratosis: where do we stand and where is the future going to take us? Expert Opin Emerg Drugs 25, 49–58 (2020).
AUTHOR CORRESPONDENCE
Leon H. Kircik MD wedoderm@yahoo.com
