Actinic keratoses (AKs) are among the more common lesions that dermatologist treat, and while AKs are considered pre-cancerous, studies regarding AKs link to squamous cell carcinoma (SCC) and field cancerization make it imperative that these lesions are treated and that as dermatologists we stay up-to-date with all advancements in the treatment and diagnosis of AKs.

Why AKs Must Be Treated: Reviewing Recent Data

Recent studies have given us greater insight into why it's important to treat AKs.

In one study, researchers examined 14 normal non-sun-exposed skin samples, 14 normal sun-exposed skin samples, five AKs, and 15 cutaneous SCCs. The fresh tissue was snap frozen in liquid nitrogen and transported to a laboratory for RNA isolation using a nontoxic aqueous reagent designed to protect RNA from degradation. High-density gene microarray studies were then performed on all RNA samples. The research showed direct correlation of abnormal gene expression in the progression of normal skin to AK to SCC.1

Another recent study demonstrated prognostic significance of follicular extension in AK. The study examining 104 AKs with follicular extension noted that patients with follicular extension of AK were 1.8 times more likely to have a previous history of invasive carcinoma than patients without follicular extension. Patients with follicular extension were 11 times more likely to have a previous history of invasive melanoma than patients with AKs without follicular extension. Patients with follicular extension were more likely to be male, had an older average age, and more often presented with lesions on their legs when compared to patients with AKs lacking follicular extension.2

A study published in 2016 showed actinic keratosis may be a marker of field cancerization in excision specimens of cutaneous malignancies. Examining 149 excision specimens of basal cell carcinoma (BCC), SCC, and malignant melanoma (MM), chi-square analysis determined that AKs were observed significantly more often (p=.0125) in SCC re-excisions (57% of 61 SCCs) than BCC (33% of 64 BCCs) or MM (33% of 24 MMs) re-excisions

Multivariate regression analysis determined the following variables to be significant in prediction of AKs near malignancies: cancer type of SCC (p=.007) and any type of cutaneous cancer located on the head (p=.044) or on the arms (p=.042).3

A 2009 Veterans Affairs study4 looked at the role AKs may play in the overall burden of keratinocyte carcinomas (KC). Data were obtained from participants in the Dept. of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Participants were examined every six months for up to six years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken to map and track the presence, absence, or biopsy of each AK across visits.

For this study, 7,784 AKs were identified on the face and ears of 169 participants. The research found the risk of progression of AK to primary SCC (invasive or in situ) was 0.60 percent at one year and 2.57 percent at four years. Approximately 65 percent of all primary SCCs and 36 percent of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. Fifty-five percent of AKs that were followed clinically were not present at the one-year follow-up, and 70 percent were not present at the five-year follow-up.4

The authors quantified the malignant potential of clinically diagnosed AKs for SCC and BCC, although many did not persist, and the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.4 Understanding the importance of treating AKs and designing the best treatment approach is key.

The Best Treatment Course: Timed Sequential Therapy

A concept I introduced about two years ago for the treatment of AKs is something called timed sequential therapy. With timed sequential therapy, we're combining two modalities that we already use, cryosurgery or another destructive modality such as photodynamic therapy (PDT), with a field therapy. Based on studies of topical AK therapies, including 5-fluorouracil, ingenol mebutate gel, or imiquimod, we know patients do better when we combine a destructive modality with a topical therapy.

Cryosurgery and Topical Thearpies

One such effective combination for the treatment of AKs has been imiquimod 3.75% cream with cryosurgery. A multi-center study5 found that sequential treatment of cryosurgery followed by imiquimod 3.75% two weeks on, two weeks off, two weeks on was well tolerated and provided additional therapeutic benefits to cryosurgery alone. For the study, patients with a baseline of more than 10 AKs on the face were treated with cryosurgery, with some patients followed by imiquimod 3.75%. For the cryosurgery/3.75% imiquimod and cryosurgery/placebo groups, respectively, median total AK reductions were 86.5 and 50 percent, and proportions of subjects with complete clearance were 30.2 and 3.3 percent. Analyzing cryosurgery-treated lesions only, median reductions were 100 and 80 percent, and subject complete clearance rates were 59.5 percent and 29.8 percent, respectively.5

In addition, imiquimod 3.75% cream and cryosurgery is effective in the treatment of hypertrophic AKs (HAKs) on dorsal hands and forearms.6 Patients were randomized to have either their right or left dorsal hand or forearm treated with imiquimod 3.75% cream, to begin on the same day as cryosurgery for hypertrophic AK lesions, two weeks on, then two weeks off, then two weeks back on. Results indicated that the number of HAK in both treatment groups decreased over time with a more pronounced effect observed at weeks 10 and 14 in the cryotherapy/imiquimod group (P 0.0094). The number of non-HAKs in the combination therapy group increased at week 6 and then decreased over time. Lesion rates decreased in the cryotherapy alone group.6

Another study demonstrated the safety and efficacy of field treatment of AKs with ingenol mebutate gel, 0.015%, three weeks after cryosurgery.7 For the study, patients were randomized to ingenol mebutate 0.015% gel or vehicle three weeks after cryosurgery. Patients receiving ingenol mebutate had a higher complete clearance rate (60.5 percent) compared with vehicle (49.4 percent). The mean percentage reduction in number of AKs versus baseline was also higher for ingenol mebutate gel (82.7 percent vs. 75.6 percent). At five weeks, the mean composite LSR score in the ingenol mebutate group returned to a score similar to that of earlier visits, which allows the use of this medication in a sequential fashion.7

A different study first presented at the 2014 Fall Clinical Conference and published in 2016, evaluated the potential benefits of treating patients with an additional three-day cycle. At eight weeks, overall clearance was 61.6 percent (277/450) for patients who received one cycle of treatment.

After a second treatment cycle, significant reductions in AK lesion counts were observed at eight weeks in patients treated with ingenol mebutate vs vehicle, both in patients with AKs present at the initial eight-week efficacy evaluation and in those with emergent AKs. Of the 340 completers who were treated twice with ingenol mebutate or once and remained clear at eight, 26, and 44 weeks, 50% were estimated to be clear of AKs at 12 months.

Ingenol mebutate 0.05% gel was also evaluated when used after cryotherapy to treat hypertrophic AKs on dorsal hands. An investigator-blinded split arm study evaluated 16 subjects with actinic keratoses on dorsal hands.8 Subjects received cryosurgery to all HT AKs on both dorsal hands at their baseline visit. Following cryosurgery, subjects were randomized by unblinded site personnel to treat either the right or left dorsal hand with ingenol mebutate 0.05% gel. There was a mean reduction in the number of hypertrophic and non-hypertropic AK lesions in ingenol mebutate-treated versus control group. A statistically significant and clinically meaningful difference in response was demonstrated in favor of ingenol mebutate-treated hands versus controls. No significant increase in local skin responses was noted when applying ingenol mebutate 0.05% gel on the same day as cryosurgery.8

Cryosurgery with 5-FU has also been shown to be safe an effective. A 2004 multicenter, randomized, double-blind, vehicle-controlled trial studied the effectiveness of cryotherapy with 5-FU vs cryotherapy with vehicle.9 The results showed at four weeks, mean AK lesion count reduced by 62.4 percent with 5-FU vs 28.8 percent with vehicle. Complete clearance was 16.7 percent with 5-FU vs 0 percent with vehicle.9

At six months, mean lesion count reduced by 67 percent with 5-FU plus cryosurgery vs 45.6 percent with vehicle plus cryosurgery and complete clearance was 30 percent with 5-FU plus cryosugery vs 7.7 percent with vehicle plus cryosurgery.9

PDT and Topicals

In addition to cryosurgery, PDT as a destructive modality may be effective, particularly when used in combination with topicals for treating AKs. One randomized, three-group study compared the efficacy and tolerability of three treatment modalities for facial actinic keratoses.10 For this study, ubjects were randomized into one of three treatment groups: two treatments with 5-aminolevulinic acid (ALA) and PDT, one ALA-PDT treatment and one course of ingenol mebutate (ingenol mebutate) 0.015% gel daily for three consecutive days, or one course of ingenol mebutate gel alone. Subjects in the two ALA-PDT treatment group had a 97.5% mean reduction from the number of baseline actinic keratosis; ALA-PDT plus ingenol mebutate gel group had an 86.7% mean reduction; while subjects in the ingenol mebutate gel alone group had a 91.7% mean reduction from the number of baseline actinic keratoses. The study authors concluded that ALA-PDT, ingenol mebutate gel, and a combination of the two treatment modalities are successful topical therapies for the reduction of actinic keratoses on the face. The group of subjects receiving two consecutive treatments with ALA-PDT, compared to treatment with ingenol mebutate gel alone or sequentially after one course of ALA-PDT had a significantly lower mean composite LSR score and a non-significant trend for greater efficacy.10

Another study showed PDT followed by imiquimod was well tolerated and improved reduction of actinic keratoses.11 The randomized, vehicle-controlled, split-face study explored the safety and efficacy of PDT followed by imiquimod. For the study, the entire face of adults with ≥10 facial actinic keratoses were treated with photodynamic therapy with aminolevulinic acid 20% at baseline and at month 1. At month 2, imiquimod 5% cream was applied to one-half of the face and vehicle to the other half, 2-times-per-week for 16 weeks. At month 12, median lesion reductions was 89.9% versus 74.5%, respectively.11

Combination Therapy: Key to Success

As the current research shows, timed sequential therapy for AKs is a safe and effective option. Combining a destructive modality with a topical therapy offers the best short- and long-term treatment option for AKs presently. This combination treatment approach addresses clinical and subclinical AKs and increases our chances of stopping the progression of AK to SCC.

Article based on Dr. Goldenberg's presentation at the December 2016 Mount Sinai meeting in New York.

Gary Goldenberg, MD is Assistant Clinical Professor of Dermatology, Mount Sinai School of Medicine, and the Medical Director of the Dermatology Faculty Practice.

1. Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of disease progression. Arch Dermatol. 2010 Mar;146(3):288-93.

2. Pandey S, Mercer SE, Dallas K, Emanuel PO, Goldenberg G. Evaluation of the prognostic significance of follicular extension in actinic keratoses. J Clin Aesthet Dermatol. 2012 Apr;5(4):25-8.

3. Lanoue J, Chen C, Goldenberg G. Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies. Cutis. 2016 Jun;97(6):415-20.

4. Criscione VD1, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF; Department of Veteran Affairs Topical Tretinoin Chemoprevention Trial Group. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30. doi: 10.1002/cncr.24284.

5. Jorizzo JL, Markowitz O, Lebwohl MG, Bourcier M, Kulp J, Meng TC, Levy S. A randomized, double-blinded, placebocontrolled, multicenter, efficacy and safety study of 3.75% imiquimod cream following cryosurgery for the treatment of actinic keratoses. J Drugs Dermatol. 2010 Sep;9(9):1101-8.

6. Goldenberg G, Linkner RV, Singer G, Frankel A. An Investigator-initiated Study to Assess the Safety and Efficacy of Imiquimod 3.75% Cream When Used After Cryotherapy in the Treatment of Hypertrophic Actinic Keratoses on Dorsal Hands and Forearms. J Clin Aesthet Dermatol. 2013 Feb;6(2):36-43.

7. Berman B, Goldenberg G, Hanke CW, Tyring SK, Werschler WP, Knudsen KM, Goncalves J, Larsson T, Skov T, Swanson N. Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results. J Drugs Dermatol. 2014 Feb;13(2):154-60.

8. Hashim PW, Nia JK, Singer S, Goldenberg G. An Investigator-initiated Study to Assess the Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryosurgery in the Treatment of Hypertrophic Actinic Keratosis on Dorsal Hands. J Clin Aesthet Dermatol. 2016 Jul; 9(7): 16–22.

9. Jorizzo J, Weiss J, Furst K, VandePol C, Levy SF. Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol. 2004 Jul;140(7):813-6.

10. Berman B, Nestor MS, Newburger J, Park H, Swenson N. Treatment of facial actinic keratoses with aminolevulinic acid photodynamic therapy (ALA-PDT) or ingenol mebutate 0.015% gel with and without prior treatment with ALA-PDT. J Drugs Dermatol. 2014 Nov;13(11):1353-6.

11. Shaffelburg M. Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream.cJ Drugs Dermatol. 2009 Jan;8(1):35-9.