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.

by David M. Pariser, MD

Dr. Pariser is with the Department of Dermatology at Eastern Virginia Medical School and Virginia Clinical Research, Inc. in Norfolk, Virginia.

FUNDING: Funding was provided by an unrestricted grant from Biofrontera.

DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article.

ABSTRACT: There have been multiple direct and indirect comparison studies evaluating different field therapies used in the treatment of actinic keratosis (AK). A recent clinical trial directly compared 5% fluorouracil (5-FU), imiquimod, ingenol mebutate, and methyl aminolevulinate photodynamic therapy (MAL-PDT), reporting that 5-FU was superior to the other treatments in achieving sustained clearance of 75 percent or greater of AK lesions compared to baseline. In this commentary, the author reviews and discusses the methods and results of this comparison study and propose these results are limited by a number of factors, such as the selected primary % clearance endpoint, grade range of included AKs, and treatments included in the comparison, when considered in the context of other clinical and real-world comparison studies evaluating AK field therapies. The author postulates that patient acceptance of and adherence to field therapy regimens for the treatment of AK may be better evaluated in a real-world setting. Additionally, the author suggests that selection of field therapy in the treatment of AK should be driven by consideration of relevant patient-, disease-, and treatment-related factors, and what is considered best may differ from patient to patient, depending on each patient’s individual needs and expectations.

Keywords: Compliance, 5-fluorouracil, photodynamic therapy, diclofenac, ingenol mebutate, imiquimod, cancerization

Actinic keratosis (AKs) is one of the most prevalent diagnoses in dermatology and is expected to rise in frequency with the aging population and increased exposure to sunlight.1 In 2015, over 35 million cases of AK were treated in the Medicare Part B fee-for-service population, highlighting the treatment burden of this condition.2 Current researchers regard AK lesions as early squamous cell carcinoma and, as such, should be treated.3

Field-directed therapy is desirable for treating AKs due to the high recurrence rate for cutaneous squamous cell carcinoma (cSCC) when therapy is only lesion-directed.4 Commonly used approaches of field therapy for AKs include 5-fluorouracil (5-FU), topical nonsteroidal anti-inflammatory drugs e.g., (diclofenac sodium, piroxicam), chemical peeling, immunomodulators e.g., (imiquimod and ingenol mebutate), and photodynamic therapy (PDT).3,5 A newly approved field treatment, tirbanibulin ointment, has also been shown to be safe and effective.6 

Ingenol mebutate’s European Union (EU) marketing authorization was withdrawn due to increased skin cancer risk. Final results from a study comparing ingenol mebutate with imiquimod indicated a higher occurrence of skin cancer with the former agent.7

Different options for field therapy have been compared in multiple meta-analyses which have provided variable results. One network meta-analysis which included results from 25 trials and 5,562 patients, indicated that aminolevulinic acid (ALA-PDT) delivered as a gel (BF-200) had the highest efficacy for complete clearance followed by imiquimod and 5-FU.8 This European meta-analysis excluded trials evaluating the 20% ALA stick because it has not been approved in Europe. However, the author includes this treatment in a sensitivity analysis to assess its relative efficacy, and according to this analysis, the BF-200 ALA PDT remained the treatment with the highest ranking, followed by imiquimod, ALA stick PDT, and 5-FU. A second meta-analysis that included results from 32 studies and 6,473 patients and employed complete clearance as an endpoint resulted in the following ranking: 5-FU > ALA-PDT > imiquimod > ingenol mebutate = methyl aminolevulinate (MAL)-PDT.9 A recent retrospective real-world chart compared 5-FU, ingenol mebutate, imiquimod, cryosurgery alone, and cryosurgery in combination with one of the topical modalities (PDT was not included in this study). Cryosurgery in combination with a topical modality provided slightly better results than any individual modality in the mean reduction of AKs.10 Current guidelines provide no clear recommendations about which approach should be used11,12 and the choice of treatment often depends on the preferences of patients and their treating physicians. While meta-analyses provide potentially useful information, they are not generally viewed as a substitute for direct comparison of treatment alternatives in controlled clinical trials.13 

A recent study was carried out to fill this gap by directly comparing four approaches to field therapy: 5-FU cream, imiquimod cream, MAL-PDT, and ingenol mebutate gel.14 While addressing an important clinical issue, this trial also raised several questions that demand consideration. This brief review addresses the results of this study in the larger context of clinical and real-world studies concerning with field therapy for AKs.

Direct comparison of field therapies

The 12-month, randomized controlled trial carried out by Jansen et al14 compared treatment success of 5% 5-FU cream, 5% imiquimod cream, MAL-PDT, and 0.015% ingenol mebutate gel in patients with AK lesions of any grade. The primary outcome of this trial was the proportion of patients who remained free from treatment failure (defined as a reduction of greater than or equal to 75% in the number of AK lesions counted at baseline occurring at 3 months after the last treatment [initial failure] or at 12 months after initially successful treatment). A total of 624 patients were included in the trial. At 12 months, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received 5-FU (74.7%) than among those who received imiquimod (53.9%), MAL-PDT (37.7%), or ingenol mebutate (28.9%) ( less than or equal to 0.001 for all comparisons). 

There are several aspects of the design and results from this study that deserve comment. First, the primary endpoint (achievement of greater than or equal to 75% clearance of lesions) was somewhat unusual. Most recent controlled trials that have evaluated field therapies for AKs have used complete clearance as a primary endpoint,15-20 and this was also the endpoint employed in the two network meta-analyses described above.8,9 Results for complete clearance were not reported by Jansen et al.14 Second, results from the study of Jansen et al appear to differ from those obtained for the same agents evaluated in other clinical trials. For example, the clearance rate for MAL-PDT has been reported to be as high as 82 percent.21 The pivotal clinical trials for imiquimod reported complete clearance rates of 35.6 percent and 30.6 percent. However, clearance of greater than or equal to 75 percent of lesions (the endpoint employed by Jansen et al) was 59.4 percent and 48.1 percent.22 Combined results from four controlled clinical trials for ingenol mebutate indicated a complete clearance rate of 42.2 percent and greater than or equal to 75 percent clearance in 63.9 percent for lesions on the face and scalp.23 Prior clinical trials of 5% FU have reported complete clearance rates ranging from 38 percent to 43 percent.24,25 

The recent real-world chart review showed a 19-percent complete clearance rate for 5-FU, 31.8 percent for ingenol mebutate, and 35.7% for imiquimod, along with 75 percent clearance of 51.7 percent, 72.7 percent and 57.1 percent respectively, which are more in line with the pivotal trials.10

The reasons for the differences between the results from Jansen et al and those from other trials are not clear, but may be related to the “slight curettage” that was performed on all lesions in study of Jansen et al.3 Debridement prior to therapy is usually only carried out in conjunction with PDT. Jansen et al included Grade I to III AKs, while other clinical studies typically included patients with Grade I or II AKs. In addition, some patients declined a second treatment, which could also explain the difference in efficacy results. For example, the MAL prescribing information specifically recommends a retreatment in cases of noncomplete lesion response. Similar applies to imiquimod and ingenol mebutate, but is not specified for 5-FU.

While Jansen et al included four commonly used approaches to field therapy in their trial, others were left out. For example, BF-200 ALA (a nano-emulsion gel containing 7.8% 5-aminolevulinic acid) has been shown to be superior to MAL-PDT and to demonstrate significantly higher efficacies after three months and significantly lower recurrence rates after one year.26-28 In addition, a patient complete clearance rate of 91 percent has been reported for this treatment.15 Diclofenac is also used frequently as field treatment for AKs,29 but was not included in the analysis. Several studies have also shown that the combination of 5-FU and ALA-PDT is highly effective for the treatment of AKs, and it would have been of interest to compare one of these regimens with AK monotherapy.30,31

Translating clinical trial results to real-world practice 

It was difficult to recruit patients for the Jansen et al study. A total of 1,174 patients were assessed for eligibility and 550 declined to participate, most often due to preference or disfavor regarding one or more of the studied treatments (197 patients).14 Thus, acceptance of therapy, an important consideration in real-world clinical practice, was a significant barrier to enrollment of patients into this study. The same applies for 5-FU retreatment in case of initial treatment failure. Another 4-week 5-FU treatment course is not common and not real-world clinical practice. Adherence is an important issue in the treatment of AKs, and it varied across treatments evaluated by Jansen et al. The percentages of patients with 100-percent adherence were 98.7 percent for the imiquimod group, 88.7 percent for 5-fluorouracil (each of these required 4 weeks of treatment), 88.2 percent for the ingenol mebutate group, and 96.8 percent for MAL-PDT. The differences between imiquimod versus 5-FU and MAL-PDT versus 5-FU were statistically significant (P=0.001 and P=0.007, respectively). Adherence to therapy in the clinical practice is likely to be significantly lower. A community-based, cross-sectional study included 305 patients with AKs who were currently using a patient-applied topical therapy (diclofenac sodium 3% gel, 5-FU 5% cream, imiquimod 5% cream, or 5-FU 5mg/g and salicylic acid 100mg/g solution) or had used one within the previous 12 months. Overall, 88 percent of patients were either nonadherent, nonpersistent or both to topical therapy. The results from this study also showed that treatments administered for less than four weeks had better patient adherence than those that required use for more than four weeks.32 A systematic review of the literature indicated that nonadherence and nonpersistence rates in real-world studies varied from 10 to 63 percent and 23 to 31 percent, respectively. Key contributing factors to nonadherence and nonpersistence to AK treatment included treatment duration, severity and persistence of local skin responses, and patient confusion over treatment regimens.33 Assessment of physicians opinion regarding AK treatment indicated that long duration of treatment and local skin reactions were viewed as the two most important reasons for nonadherence.34

Since it is not always possible to clear each AK lesion in real-life practice, the main aim of therapy is to reduce the number of lesions and to achieve long-term disease control.35 In the clinical setting, physicians should select AK treatments based on local availability and the presentation and needs of their patients.35 Patient acceptance of and satisfaction with treatment are important considerations that can influence adherence and treatment success, and cosmetic results are an important determinant of acceptance of therapy for AKs.36 In the study of Jansen et al, at 12 months post-treatment, a good-excellent cosmetic result was recorded for 90.3 percent patients treated with 5-FU, and for 89.7 percent, 96.6 percent, and 95.1 percent of the patients treated with ingenol mebutate, MAL-PDT, and imiquimod, respectively. Percentages were highest for MAL-PDT and imiquimod, and the difference between 5-FU and MAL-PDT was significant (P=0.033). Impact on quality of life is also an important consideration. At 12 months post-treatment, the median decrease in Skindex-29 score from baseline was -4.31 for 5-FU, -3.88 for imiquimod, -2.59 for MAL-PDT, and -3.45 for ingenol mebutate. P-values comparing 5-fluorouracil with imiquimod, MAL-PDT, and ingenol mebutate were P=0.68, P=0.002, and P=0.20, respectively.14


Overall, available results continue to support the view that selection of field therapy for AKs and field cancerization should be driven by consideration of relevant patient-, disease-, and treatment-related factors, and that appropriate treatment decisions will differ from patient to patient.37 The study by Jansen et al contradicts multiple well-controlled studies and raises questions that should be taken into consideration when including the conclusion of the comparison into the decision process. Developing a roadmap to guide effective care of patients with AKs requires careful consideration of the entire body of clinical evidence supporting every approved intervention along with understanding patient- and treatment-related factors that may significantly influence acceptance of and adherence to therapy.


Medical writing and literature research was provided by AraMed Strategies.


  1. Lim HW, Collins SAB, Resneck JS, et al. The burden of skin disease in the United States. J Am Acad Dermatol. 2017;76(5):958–972.e2. 
  2. Yeung H, Baranowski ML, Swerlick RA, et al. Use and cost of actinic keratosis destruction in the Medicare Part B fee-for-service population, 2007 to 2015. JAMA Dermatol. 2018;154(11):1281–1285. 
  3. Dianzani C, Conforti C, Giuffrida R, et al. Current therapies for actinic keratosis. Int J Dermatol. 2020;59(6):677–684. 
  4. Huang A, Nguyen JK, Austin E, et al. Updates on treatment approaches for cutaneous field cancerization. Current Dermatol Rep. 2019;8(3):122–132. 
  5. Diepgen TL, Eicke C, Bastian M. Ingenol mebutate as topical treatment for actinic keratosis based on a prospective, non-interventional, multicentre study of real-life clinical practice in Germany: efficacy and quality of life. Eur J Dermatol. 2019;29(4):401–408.
  6. 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. 
  7. EMA. Picato (ingenol mebutate) – Suspension of the marketing authorisation due to risk of skin malignancy. Available at: Date accessed: April 1st, 2021
  8. Vegter S, Tolley K. A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PloS one. 2014;9(6):e96829. 
  9. Gupta AK, Paquet M. Network meta-analysis of the outcome “participant complete clearance” in non-immunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169(2):250–259. 
  10. Hansen JB, Larsson T, Dunkelly-Allen N, et al. Real-world effectiveness and safety of field- and lesion-directed treatments for actinic keratosis. J Drugs Dermatol. 2020;19(8):756–762. 
  11. Werner RN, Stockfleth E, Connolly SM, 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. 2015;29(11):2069–2079. 
  12. Berker D de, McGregor JM, Mohd Mustapa MF, et al. British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol. 2017;176(1):20–43. 
  13. Tur C, Kalincik T, Oh J, et al. Head-to-head drug comparisons in multiple sclerosis: urgent action needed. Neurology. 2019;93(18):793–809. 
  14. 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. 
  15. Reinhold U, Dirschka T, Ostendorf R, 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(4):696–705. 
  16. Carbotti M, Coppola R, Zanframundo S, et al. Efficacy of ingenol mebutate in the treatment of actinic keratoses: a pre- and posttreatment dermoscopic comparative analysis. Biomed Res Int. 2018;2018:4381019. 
  17. Saraiva MIR, Portocarrero LKL, Vieira MAHB, et al. Ingenol mebutate in the treatment of actinic keratoses: clearance rate and adverse effects. An Bras Dermatol. 2018;93(4):529–534. 
  18. Yang C-C, Wong T-W, Lee C-H, et al. Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: a Phase III randomized double-blind vehicle-controlled parallel trial. J Dermatol Sci. 2018;90(3):295–302. 
  19. Kim YC, Yang JY, Yoon JS, et al. A multi-centre, open, investigator initiated phase IV clinical trial to evaluate the efficacy and safety of ingenol mebutate gel, 0.015% on the face and scalp, and 0.05% on the trunk and extremities, in Korean patients with actinic keratosis (PERFECT). Br J Dermatol. 2018;179(4):836–843.
  20. Togsverd-Bo K, Halldin C, Sandberg C, et al. Photodynamic therapy is more effective than imiquimod for actinic keratosis in organ transplant recipients: a randomized intraindividual controlled trial. Br J Dermatol. 2018;178(4):903–909. 
  21. Torezan L, Grinblat B, Haedersdal M, et al. A randomized split-scalp study comparing calcipotriol assisted MAL-PDT with conventional MAL-PDT for the treatment of actinic keratosis. Br J Dermatol. 2018;179(4):829–835. 
  22. Swanson N, Smith CC, Kaur M, Goldenberg G. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: two phase 3, multicenter, randomized, double-blind, placebo-controlled studies. J Drugs Dermatol. 2014;13(2):166–169.
  23. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010–1019.
  24. Pomerantz H, d. Hogan, 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. 
  25. Loven K, Stein L, Furst K, Levy S. 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. 2002;246):990–1000.
  26. Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166(1):137–146.
  27. Dirschka T, Radny P, Dominicus R, et al. Follow-up analysis of the efficacy of photodynamic therapy in actinic keratosis. Br J Dermatol. 2013;168(4):825–836. 
  28. Dirschka T, Ekanayake-Bohlig S, Dominicus R, 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. J Eur Acad Dermatol Venereol. 2019;33(2):288–297. 
  29. Asche CV, Zografos P, Norlin JM, et al. Evaluation of resource utilization and treatment patterns in patients with actinic keratosis in the United States. Value Health. 2016;19(2):239–248.
  30. Martin G. Prospective, case-based assessment of sequential therapy with topical fluorouracil cream 0.5% and ALA-PDT for the treatment of actinic keratosis. J Drugs Dermatol. 2011;10(4):372–378.
  31. Pei S, Kaminska ECN, Tsoukas MM. Treatment of actinic keratoses: a randomized split-site approach comparison of sequential 5-fluorouracil and 5-aminolevulinic acid photodynamic therapy to 5-aminolevulinic acid photodynamic monotherapy. Dermatol Surg. 2017;43(9):1170–1175. 
  32. Shergill B, Zokaie S, Carr AJ. Non-adherence to topical treatments for actinic keratosis. Patient Prefer Adherence. 2013;8:35–41. 
  33. Foley P, Stockfleth E, Peris K, et al. Adherence to topical therapies in actinic keratosis: A literature review. J Dermatolog Treat. 2016;27(6):538–545. 
  34. Stockfleth E, Peris K, Guillen C, et al. Physician perceptions and experience of current treatment in actinic keratosis. J Eur Acad Dermatol Venereol. 2015;29(2).298–306.
  35. 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. 
  36. Cerio R. The importance of patient-centred care to overcome barriers in the management of actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:17–20. 
  37. Hofbauer G, Anliker M, Boehncke WH, et al. Swiss clinical practice guidelines on field cancerization of the skin. Swiss Med Wkly. 2014;144:w14026.