Reformulated drugs for actinic keratosis address issues with field therapy

Maui, Hawaii - New topical agents such as ingenol mebutate (Picato, Leo Pharma), reformulations of standing local treatments as well as combination therapies are not only proving to be very useful in the clearance of actinic keratosis (AK), but they also help address the common issues regarding field therapy.

Although field therapy has become widely recognized as a wise treatment approach in patients with multiple AKs, George Martin, M.D., says the technique still remains an underutilized therapy for patients with significant actinic damage.

“Actinic keratosis is a chronic disease and field therapy is imperative because we do not know which of these lesions will evolve into invasive squamous cell carcinoma (SCC),” says Dr. Martin, Dermatology and Laser Center of Maui, Kihei, Hawaii. Dr. Martin spoke at MauiDerm.

Prolonged downtime - which can range from weeks to months - patient compliance issues, drug costs, and patient discomfort during extended therapy all factor into the underutilization of field therapies. In varying degrees, these issues are associated with all of the currently used topical treatment approaches including imiquimod, 5-fluorouracil (5-FU), diclofenac and photodynamic therapy (PDT).

Fast and effective

According to Dr. Martin, newer therapies with shorter downtime - such as ingenol mebutate and short duration 5-FU 0.5 percent cream - as well as combination therapies with combined efficacy and minimal downtime have been developed to address these limiting factors of treatment.

Available in 0.015 percent and 0.05 percent gel strengths, ingenol mebutate is a game-changer, Dr. Martin says, because it only has to be applied on the field area once daily for two to three consecutive days, resulting in a good compliance by patients.

“Ingenol mebutate 0.015 percent applied nightly for three consecutive days to the face or scalp has been a remarkably effective therapy with great patient compliance for not only limited areas (25 cm²), as demonstrated in phase 3 clinical trials, but even when applied over the entire face,” he says. “Clinically there appears to be selectivity for AKs with normal areas between the AK lesions. In my hands, it has been a very effective full-face field therapy with limited downtime.”

The mechanism of action of ingenol mebutate appears to involve a direct cytotoxic effect, Dr. Martin says, which takes place in the first 24 hours, accompanied by an upregulation of interleukin-8 (IL-8), resulting in neutrophil migration. Patients should expect some burning and irritation in the treated area typically starting around four hours after the application of the gel, and a downtime of approximately 10 days.

Patient compliance

The recommended protocol for imiquimod 5 percent cream (Aldara, Medicis) is twice a week for 16 weeks, which, according to Dr. Martin, can raise issues of compliance in patients. This led to the development of imiquimod 2.5 percent and 3.75 percent cream (Zyclara, Medicis) formulations, which now allow for much shorter treatment times when administered in the recommended two weeks on, two weeks off, two weeks on regimen.

“These protocols make imiquimod easier to comply with as they are shorter but there is still some significant downtime, particularly when compared to ingenol mebutate,” Dr. Martin says.

Though the one-week downtime associated with PDT treatment is the shortest of the topical therapies, Dr. Martin says PDT remains one of the more painful treatments in AK therapy and requires premedication, sometimes making patients prefer other, more “gentle” therapeutic options such as 5-FU, imiquimod and now, ingenol mebutate.

One of the cornerstone field therapies for facial AK lesions is topical 5-FU. To shorten treatment times and downtimes while maintaining efficacy, Dr. Martin asks his patients to apply 0.5 percent 5-FU (Carac, Valeant) QD for one week, wait one month, and then continue with two weeks of therapy. According to Dr. Martin, this regimen has gained widespread acceptance by patients and physicians as a more tolerable, yet effective, field therapy.

“In my experience, ingenol mebutate, short-course 5-FU and PDT are some of the more ideal AK treatment approaches in respect to efficacy, efficiency, cost and downtime,” he says. “The choice of treatment however should be made according to the individual patient’s needs.”

Disclosures: Dr. Martin is a consultant for Leo Pharma and Valeant. He is a speaker for and serves on the scientific ad boards for Leo Pharma, Valeant and Medicis.