What’s new in treating actinic keratosis?

By Allison Evans, Assistant Managing Editor, November 1, 2022

Actinic keratoses (AKs) are commonly diagnosed and treated by dermatologists. In fact, the National Ambulatory Medical Care Survey on outpatient medical care in the U.S. found that AK was the second-leading diagnosis at dermatology visits.

Although they often persist as chronic skin lesions, AKs can spontaneously involute or evolve into keratinocyte carcinoma if left untreated. With a wide variety of treatment options — each with advantages and disadvantages — there’s much to consider when working with patients to develop a management plan.

“In general, we think about patients with AK as either people with an isolated lesion or people who have multiple AKs, in which case it’s essentially a chronic skin condition,” said Naomi Lawrence, MD, FAAD, professor of medicine at Cooper Medical School of Rowan University and head of the procedural section in the Division of Dermatology at Cooper University Health Care.

“Sometimes after an initial visit, I’ll have a patient return six-to-12 months later with more AKs feeling as though the treatment has failed,” Dr. Lawrence said. “In reality, my failure was to explain the process. We need to inform patients that this is now a chronic condition and that they will continue to develop AKs over time and will require management and surveillance.”

Treatment decisions

Treatment options for AK include field-directed therapies, such as topical medications and photodynamic therapy (PDT), and lesion-directed therapies, like cryosurgery and other destructive and surgical therapies.

“We have good treatments like cryosurgery for spot treatment, but then we have all these other treatments for field treatment like topicals, PDT, and chemical peels. The treatment selection really should be tailored to the patient and their preferences — and most importantly — what they’re going to be compliant with,” Dr. Lawrence said.

“All of our patients are different, and therefore all of our treatment recommendations should be different,” said Daniel Eisen, MD, FAAD, co-author of the Academy’s actinic keratosis clinical guideline and focused update published in JAAD. “There are a lot of different variables that go into making a recommendation: Does your patient’s insurance pay for the medication they want? Are they willing to put up with a long duration of therapy? Would they prefer a one-treatment session? Are they willing to endure more pain for better efficacy? Everybody’s values and preferences are different, so we tailor treatment according to patient values and individual situations.”

“Many dermatologists probably lean toward cryosurgery because it’s something that can be done in the office relatively quickly, and it gets the worst lesions peeled off,” Dr. Lawrence said. “Some of these other treatments like 5-fluorouracil (5-FU) have to be applied for weeks — and the longer it’s being applied, the more patients get increasingly sore and uncomfortable. There’s some good evidence that shows it’s one of the best field treatments we have, but many patients hate it, so it’s important to look at their likelihood to comply.”

“Someone with a single AK may not need to come in on a regular basis, but once someone has five or more AKs, I would say they need to be seen every four to six months,” Dr. Lawrence said. “Once patients have about 20 AKs, they should probably be receiving field treatment every one to three years.”

Guideline recommendations

In April 2021, the American Academy of Dermatology published its “Guidelines of care for the management of actinic keratosis” in JAAD. “Our committee looked at a variety of different treatments for actinic keratoses, and the evidence was looked at in a systematic way and organized according to quality of evidence,” Dr. Eisen said. “We then made recommendations that could be considered strong or conditional, depending on the level of evidence.”

“We strongly recommend the use of a few medications — 5-fluorouracil, imiquimod, and tirbanibulin, the latter of which was published as a focused update in JAAD earlier this year,” Dr. Eisen noted (doi: doi.org/10.1016/j.jaad.2022.04.013). “We also have two good practice statements, which are strong recommendations considered to clearly result in beneficial outcomes. The good practice statements recommend the use of ultraviolet (UV) sun protection and the use of cryosurgery. Conditional recommendations were made for the use of PDT and diclofenac, both individually and as part of combination therapy regimens,” he added.

Cryosurgery, destruction

“If a patient has just a few actinic keratoses, they might prefer cryosurgery because it can be taken care of right in the office, avoiding weeks of medication application,” Dr. Eisen said. “But on the other hand, if patients are covered from head to toe with AKs, you can’t freeze the entire surface of their skin.”

Clinically, cryosurgery has been reported to cure between 57% and 98.8% of AKs followed up over three months to eight-and-a-half years, with clearance rates associated with the duration of freeze. One study of cryosurgery for the treatment of AKs on the face or scalp reports complete clearance rates of 39%, 69%, and 83% for freeze times of less than five seconds, five to 20 seconds, and greater than 20 seconds, respectively.

Laser ablation is another option that is not as widely used as cryosurgery. A study comparing the two treatments favored cryosurgery for both lesion reduction and complete clearance. Surgical therapies, such as shave excision or curettage, are typically reserved for hyperkeratotic lesions.

Topical field therapies

“If somebody is manifesting AKs on their skin surface, then it is likely that all sun-exposed skin has some dysplasia or some disordered growth,” explained Dr. Lawrence. “The AKs are just coming from the most disordered growth. The reason why field treatment makes sense is that you may want to treat all of the skin in the area to try and prevent other AKs from forming.”

“The most common obstacle with field treatment, aside from the adverse events, is simply convincing a patient that I don’t just need to just treat the little scaly spots; I need to treat the skin in between,” Dr. Lawrence said. “Even when you do treat that skin, usually somewhere between one year and three years, you’re going to have to do it again.”

While 5-FU and imiquimod have shown good efficacy for clearing AKs, they come with an adverse event profile that may be intolerable to some patients. “You spend a lot of time counseling patients to expect a pretty robust reaction. It’s going to turn red; it may get tender; and the area may blister up,” Dr. Eisen said. “All of that is expected, but even so, you still end up with lots of phone calls because patients typically aren’t prepared for that situation.”

5-Flurouracil (5-FU)

5-FU is available as a cream at 5%, 1%, and 0.5%, or in a solution at 5% and 2%. The most common treatment regimen is applying the 5% cream twice daily for two-to-four weeks. In a meta-analysis of five randomized controlled trials, treatment with 5% 5-FU led to an average complete clearance rate of 49%. 5-FU is used to treat a single lesion or large areas, providing a complete clearance rate at eight weeks ranging from 96% in patients treated with 5% 5-FU to 48% in those receiving 0.5% 5-FU cream (doi: doi.org/10.1007/s40257-022-00674-3).

Imiquimod

Imiquimod is available as a 5% cream, which is applied twice weekly for up to 16 weeks, with a meta-analysis of five trials showing complete clearance in 50% of patients. There is also a 3.75% or 2.5% formulation applied nightly for two weeks, followed by a two-week rest period, then another two-week treatment period. The lower concentration is meant for shorter treatment duration as well as larger treatment area (200 cm2) and may have reduced efficacy with large-scale clinical trials showing a clearance rate of 36%.

Diclofenac

Topical diclofenac 3% is available in a gel that is applied twice daily for 60 to 90 days, said Dr. Schlesinger, which is a prolonged treatment period. An advantage of diclofenac, however, is the relatively mild cutaneous effects compared with other therapies such as 5-FU. A meta-analysis of three trials showed that the treatment led to complete clearance in 40% of patients.

Photodynamic therapy

The primary benefit of photodynamic therapy (PDT) is that it is a physician-provided treatment. “You don’t have to worry about compliance. Patients receive the treatment once and then they go home and have a mild sunburn for a week. That can be a lot more tolerable than some of these field therapies,” said Dr. Eisen, who prefers PDT to some of the topicals.

There are many regimens for treatment with PDT, including variations on incubation time of typically between one to three hours — with studies showing at least a two-hour incubation period for optimal lesion reduction. “It’s important to remember that most PDT is used off label,” said Todd Schlesinger, MD, FAAD, co-author of the Academy’s actinic keratosis clinical guideline and focused update.

“The primary sensitizing agent for PDT protocols in the U.S. is 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) outside the U.S.,” he added, “although some dermatologists may be using daylight PDT, which has been associated with minimal pain.”

A network meta-analysis comparing the relative efficacy of 10 AK treatments, including topical therapies and PDT, concluded that ALA-PDT showed the highest efficacy compared to placebo to achieve complete patient clearance of AKs. “However, because the overall quality of evidence is low, the guideline work group conditionally recommends ALA-red light PDT,” Dr. Schlesinger said.

5-FU and calcipotriene

“An emerging combination therapy is the addition of calcipotriene to 5-FU, which really shortens the treatment course,” Dr. Lawrence said. “Studies have shown that this combination can be used twice a day for only four days, although in real practice, we typically recommend five-to-seven days to induce an adequate response.”

“While the AAD clinical guideline did not include a recommendation for this treatment due to lack of data, many dermatologists feel like this helps their patients tolerate 5-FU,” Dr. Schlesinger said.

In a randomized controlled trial, 5-FU combined with calcipotriol resulted in a mean reduction in the number of AKs of 87.8% on the face, 76.4% on the scalp, 68.8% on the right upper extremity, and 79% on the left upper extremity, respectively.

“The higher efficacy of 5-FU combined with calcipotriol was associated with significantly higher percentages of participants reporting skin redness and burning but not scaling or itching during the four-day treatment period. Treatment with calcipotriene is associated with more inflammation than 5-FU alone and peels 10 days after the initiation of treatment, which usually resolves by two weeks,” Dr. Lawrence said.

Additional options

Another option that may prove effective for some patients with AKs are chemotherapeutic wraps, or chemowraps, which are most often used to treat the lower legs and forearms. “If a patient has legs full of AKs, using 5-FU and wrapping the leg with zinc-impregnated gauze can help,” Dr. Lawrence noted. “You have to be careful because if there’s too much absorption of the 5-FU, patients can show some toxicity. You don’t want to wrap too large of an area; I tend to wrap one lower leg at a time.”

“Chemo wraps are usually continued for four weeks, with the wraps changed weekly. Because of the mode of application, patient compliance is high. However, patients cannot bathe for a week, which can hinder patients from considering this as treatment,” she said. Alternatively, dermatologists may also consider using 5-FU twice daily for four weeks with occlusion overnight with a plastic wrap, she added.

“I also do quite a few medium-depth chemical peels, which work well because I treat a large skin cancer population with a lot of older patients who don’t want to have to put something on at home,” Dr. Lawrence said. “I have them use a retinoid for two weeks beforehand to help prepare their skin for the peel.”

“The other thing you can recommend to your patients with AKs, and this isn’t directly to treat the AKs but to decrease the number of AKs that might turn into skin cancers, is nicotinamide, which is a B3 derivative,” she said. “There are some good studies that show that taking 500 milligrams two or three times a day can decrease the incidence of AKs and SCCs.”

The newest treatment

At the end of 2020, the FDA approved the microtubule inhibitor tirbanibulin 1% ointment for the treatment of AKs on the face and scalp. While the studies seem to show good efficacy, the price of the medication is extremely high, Dr. Eisen said. In August, GoodRx showed an average retail price of about $1,200 without insurance. “If you’re paying out of pocket, that’s not even a possibility for the vast majority of people.”

“Additionally, most insurance does not cover the drug, so until the price comes down, I don’t see it becoming a widely used treatment,” Dr. Lawrence added.

One of the benefits to tirbanibulin, Dr. Eisen noted, is that there’s a relatively short duration of treatment compared to 5-FU or imiquimod. It only needs to be applied for five consecutive days as opposed to weeks of treatment with other field therapies.

While the data look promising, there are currently no comparative effectiveness studies for this treatment, Dr. Schlesinger noted, although there is an ongoing phase 4 clinical trial evaluating the incidence of invasive squamous cell carcinoma after being treated with 10 mg/g tirbanibulin or diclofenac sodium 3% gel.

Progression to SCC

It is widely accepted that AKs represent the initial manifestations in a continuum that may eventually progress to squamous cell carcinoma (SCC). Studies suggest the overall risk is approximately 8%, although the likelihood varies with age, gender, chronic UV exposure, and location of AKs.

“There’s been a few studies, but they haven’t really been ideally designed to answer the question of what percentage of AKs will turn into an SCC,” Dr. Eisen said.

“We know people with AKs have developed SCCs, but the risk of a single AK to progress is quite low,” Dr. Lawrence said. “However, it is clear that those with multiple AKs have a higher risk of developing SCC. This is especially concerning if patients are older or immunosuppressed, which predisposes them to a higher rate of progression to SCC. For those who are immunosuppressed, it is best to be more aggressive, which often requires cyclical use of field-directed therapies.”

While it is not possible to accurately predict which AK lesions will progress to SCC, some clinical characteristics may point to an increased risk of malignancy, including induration/inflammation, lesion diameter greater than 1 cm, rapid enlargement, bleeding, erythema, and ulceration.

Dr. Weinstock and colleagues showed that after a course of 5-FU, the risk of getting an SCC was 75% less at one year and 11% less for BCC, although the risk for basal cell wasn’t statistically significant (doi: 10.1001/jamadermatol.2017.3631). “They also found that people who had a course of 5-FU were less likely to need Mohs surgery, which illustrates the potential benefits of these treatments,” Dr. Eisen noted.

Tools in the toolbox

“We have a lot of treatments in our toolbox, although none of them are perfect,” Dr. Lawrence said. “The downside is that the benefit of treatment is lost with time. Treating AKs is more than just a one-time treatment. These patients will need to be followed and treated throughout the course of their lives,” Dr. Eisen added.

“For a long time, the unmet need for AKs has been a treatment that has a short duration of therapy with relatively few side effects and good efficacy,” Dr. Schlesinger said. “We also need more options for large-field treatment — both for face and scalp as well as areas off of the face and scalp.”

To date, there are no treatments that completely eradicate dysplasia or tendency toward developing actinic keratoses once a patient has formed multiple lesions, Dr. Lawrence said. “On a practical level, I think one of the most important aspects in managing actinic keratosis is to provide patients with realistic expectations of the treatment course to preempt common compliance issues.”

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