More options mean more opportunities for successful treatment outcomes for dermatology patients. While actinic keratoses (AKs) have a number of therapeutic options available, their effectiveness can vary and cause pain for patients, citing a need for additional modalities for the precancerous lesions.

Roger I. Ceilley, MD, is a dermatologist and director of the Mohs and dermatologic surgery training programs at Dermatology PC in West Des Moines, IA. He is dual-certified in dermatology and dermatopathology and has previously served as president of the American Academy of Dermatology and the American Society for Dermatologic Surgery.

In an interview with The Dermatologist, Dr Ceilley covered some exciting advances for AK treatment as well as discussed how dermatologists can develop a management plan.

What’s the best approach to treating AKs?
There are a number of options now available, but our therapies fall into two main categories. One would be a destructive techniques, such as freezing, burning, or scraping them off. The other method is medical or field-type treatment, which includes things such as topically applied medicines and photodynamic therapy (PDT).

We should base our treatment approach on how many lesions a patient has and the characteristics of the lesions. For example, if there are just a small number of lesions, you would not want to necessarily treat the whole face. Instead, you might freeze them off. However, if the patient has thicker lesions with a rougher surface or little horn on the surface, and this patient has not responded very well to topical treatment, then you may want to consider freezing.

In patients with a greater area of involvement, you would want to think about using one of the topical treatments or PDT. Both those options will treat the AKs that you can see or feel as well as those that are developing process or are shorter than the point of visibility. If you run your finger over the skin and it feels rough and gritty, like sandpaper, then that gives us a clue to areas that may not be visible yet. It’s also important to note that if the patient has a significant number of AK lesions, they're more likely to have skin cancers.

So, our decision to treat is based on the number of spots they have and how thick they are, but also whether you are going to treat individual spots or with field therapy, in which you would treat a whole area such as a face or balding scalp.

There are a variety of options for treatment, and an international consensus conference determined that they are all effective.¹ The choice then becomes just a matter of deciding, but unfortunately, the choice is often dictated by which therapies are covered by insurance or Medicare, not necessarily what is best for the patient.

Could you describe the current options for AKs?
Of the ones that are available now, 5-fluorouracil (5-FU) has the longest history of use. It was discovered as a potential treatment when some patients at the University of Wisconsin, who were being treated for bowel cancer, were given this medicine internally, and the treating physicians noticed that skin spots went away. Then, back in the 1960s or 1970s, they approved it for the topical treatment. A number of other products have come out in various formulations of 5-FU.

Since 5-FU, additional drugs have come along. Imiquimod is certainly one option. There are a variety of concentrations to use, from 2.5%, 3.75%, and 5%. The lower concentrations try to make imiquimod easier to use. The original regimen was to use 5% once a week or twice a week, but these lower concentrations allow patients to put it on every day for a couple of weeks, take a couple weeks off, and the repeat application. That is more convenient for patients, but again, it is a matter of whether it is covered.

Now, there have been some attempts to make AK treatment a little bit easier. Tirbanibulin is a recently approved 5-day application vs a prolonged treatment as seen in older forms of 5-FU, which when used once or twice a day for 3 weeks could cause irritation. These shorter application periods help get better compliance in order to get better results.

Current studies are exploring variations of current therapies, including different strengths of imiquimod and vitamin D. What else is in the pipeline for AKs?
Vitamin D supplementation does seem to be helpful, though its use is not standardized at all. Many of our patients with AKs tend to be older, and they may have a vitamin D deficiency because of their maturity. We also want patients to be in the sun less; if they already have AKs, their risk for skin cancer is increased. So, there is thought that these patients may not get enough vitamin D and therefore require a supplement. In vivo and in vitro research by Dr Edward Maytin and colleagues show that it may be effective to supplement with vitamin D prior to treatment.^2-5

Calcipotriene (or calcipotriol) initially was developed to treat psoriasis as a vitamin D analog for the surface of the skin. It has shown that this drug can make 5-FU much more effective, and you can treat the AKs for just 5 days.⁶ This is an a off-label combination growing in popularity, but we have to compound these two agents together. The FDA directs us to use off-label treatments as long as it is safe and effective for the patients, but the hope is, eventually, someone will come up with a branded, approved form of this combination. That would be an exciting option for our patients.

There are also some variations of this PDT that are useful for making treatment less painful or more effective. A number of modifications also are quite helpful, such as changing the amount of time between putting the drug on the skin and exposing it to light. In a recent study, light was applied almost immediately after drug application, which is vastly different from the initial 24-hour waiting period; this method was found to be effective.⁷ Research is still trying to find that sweet spot for application and timing.

There are also some new formulations of photosensitizer drugs such a gel out of Germany that is followed by red lights, instead of blue, and is quite effective and safe. Research is also exploring additional modifications of these PDT regimens for not only treating AKs but also other cancers in the body.

It’s exciting to see the level of research in this area. Whenever we can avoid doing something internally with an effective topical treatment, it is certainly a plus for us and our patients.

References
1. 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. doi:10.1111/jdv.13180

2. Rollakanti K, Anand S, Maytin EV. Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models. Proc SPIE Int Soc Opt Eng. 2015;9308:93080Q. doi:10.1117/12.2077296

3. Anand S, Rollakanti KR, Horst RL, Hasan T, Maytin EV. Combination of oral vitamin D3 with photodynamic therapy enhances tumor cell death in a murine model of cutaneous squamous cell carcinoma. Photochem Photobiol. 2014;90(5):1126-1135. doi:10.1111/php.12286

4. Sato N, Moore BW, Keevey S, Drazba JA, Hasan T, Maytin EV. Vitamin D enhances ALA-induced protoporphyrin IX production and photodynamic cell death in 3-D organotypic cultures of keratinocytes. J Invest Dermatol. 2007;127(4):925-934. doi:10.1038/sj.jid.5700595

5. Anand S, Wilson C, Hasan T, Maytin EV. Vitamin D3 enhances the apoptotic response of epithelial tumors to aminolevulinate-based photodynamic therapy. Cancer Res. 2011;71(18):6040-6050. doi:10.1158/0008-5472.CAN-11-0805

6. Rosenberg AR, Tabacchi M, Ngo KH, et al. Skin cancer precursor immunotherapy for squamous cell carcinoma prevention. JCI Insight. 2019;4(6):e125476. doi:10.1172/jci.insight.125476

7. Kaw U, Ilyas M, Bullock T, et al. A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: bilaterally controlled, randomized trial of simultaneous versus conventional illumination. J Am Acad Dermatol. 2020;82(4):862-868. doi:10.1016/j.jaad.2019.09.010