Treating the AK field

Actinic Keratosis (AK) is a chronic disease that can manifest in single or multiple lesions, including subclinical lesions that are invisible to the naked eye. In Hawaii, where the sun shines all year long, dermatologists are no strangers to patients with AK. Speaking at Maui Derm 2016, George Martin, M.D. shared some innovative refinements of conventional AK treatments.

The tip of the iceberg

Dr. MartinDr. Martin, who is a solo practitioner at Dr. George Martin Dermatology Associates of Maui, Kihei, Hawaii, says that â€Å“Clearly, singular lesions are best and most conveniently treated with liquid nitrogen. However, the presence of a single AK can be deceiving in terms of the true scope of disease because we dermatologists feel that one AK is usually just the tip of the iceberg. There are likely many subclinical AKs [i.e., field cancerization] present in normal appearing skin.â€Â

Field cancerization requires field therapy. Although there are many different modalities available for the treatment of AKs, Dr. Martin says that less than 10% of dermatologists use field therapy on their patients. Some of the reasons include the tremendous downtime associated with therapy (weeks to months) and pushback from patients because of the cosmetic side effects. The pain associated with treatment often directly impacting patient compliance.

â€Å“Unfortunately, conventional PDT can be very painful. While off-label daylight-mediated PDT can achieve upwards of 75% clearance rates and can shift the pain paradigm significantly, this approach is not feasible in the US for many reasons, including weather issues and legal issues, as well as insurance reimbursement,â€Â Dr. Martin says. The off-label, daylight-mediated approach is 30 minutes of MAL PDT followed by 1½-2½ hours of natural sunlight exposure with sunscreen.

Any one of the field therapies will result in varying degrees of oozing, crusting, and pain, which at times can be significant for some patients. Recognizing the therapeutic power, and the drawbacks, of standing agents and modalities such as PDT, Dr. Martin set out to optimize the treatment regimen by adjusting the parameters of in-office PDT therapy. Dr. Martin recently conducted a prospective split-face study¹ in 3 patients, including treatment associated pain measurements in over 100 patients with AKs, comparing short ALA incubation times of 15 minutes followed by 60 minutes of continuous blue light exposure versus traditional ALA PDT.

Next: Photos from the study

Effectiveness without pain

3.75% imiquimod QD x 1 week ;Two weeks off; Followed by Q weekly applications. 1st: Baseline. 2nd: End of 12 week tx. 3rd: 2 years later. Photo: George Martin, M.D.Data showed that after one treatment, the shorter exposure time PDT resulted in a 52% reduction of AK lesions compared to only 44% with conventional PDT. None of the shorter incubation time patients experienced significant pain (>7/10 pain scale) throughout the study, while traditional PDT patients recorded significant pain.

Pain with PDT has been related to cellular destruction and inflammation, and possibly a direct effect of PDT on nerve fibers. During treatment, PDT produces reactive oxygen species that result in tissue destruction, and it destroys AKs because of the preferential accumulation of the photosensitizing molecule protoporphyrin IX (PpIX). Shortening the incubation time and allowing PpIX to accumulate within the targeted cells (AKs) without diffusing into the surrounding tissues where the nerve endings are appears to be instrumental in mitigating the pain associated with in-office PDT treatments.

â€Å“Although the parameters can still be fine-tuned, this is a major advance for in-office painless PDT, allowing us to perform the procedure in a controlled environment, the same way you do traditional PDT on a regular basis, just without the procedural pain and logistical nightmare associated with other field therapies,â€Â Dr. Martin says.

Aside from the pain, another critical limitation of field therapy is the extended downtime associated with treatment, which can range from weeks to months and which can significantly impact patient compliance. Although PDT offers a selective advantage over the other field therapies because it has the shortest downtime, imiquimod remains one of the most used therapeutic agents for AKs primarily due to its proven immunomodulatory effect. Over the last quarter century, imiquimod has undergone changes in its concentration from the original 5% cream concentration (Aldara, Valeant) to 2.5% and 3.75% cream concentration (Zyclara, Valeant) to be used daily for 2 weeks, then 2 weeks off, and then reapply for 2 weeks.

Related information:

Off-label PDT protocols show promise

Next: Keeping AK at bay

Keeping AK at bay

Actinic keratosis—like hypertension, diabetes, and rheumatoid arthritis—is a disease that has an ongoing presence in the lives of patients. As such, Dr. Martin says that there need to be a fundamental shift in the way clinicians approach AK. Instead of treating episodically every few months whenever AKs accumulate and become visible to the naked eye in terms of field cancerization, Dr. Martin suggests that AK should be treated continually, ad infinitum.

In many of his patients with field cancerization, Dr. Martin is following a new off-label treatment regimen using 3.75% imiquimod with the goal of treating and keeping AKs at bay through continuous immunomodulatory stimulation. Here, AK patients apply imiquimod every day for one week, have 2 weeks off—allowing the crusts and peeling to subside—then follow-up with once-a-week imiquimod application, indefinitely.

â€Å“In addition to the great clearance achieved with this approach, we’ve also witnessed very long-remissions. Most of my patients on this regimen have stayed clear for over 2 years and counting, which is very rarely seen with traditional prescribed treatment regimens,â€Â Dr. Martin says.

Ideally, the patients who would benefit most from this continuous AK therapy would be those with moderate to severe disease. Here, Dr. Martin says that those patients with field cancerization could receive a combined therapy consisting of in-office painless ALA PDT to clear the bulk of the lesions, followed with long-term application of 3.75% imiquimod cream for longer remission.

â€Å“We need to optimize our current therapies and in select patients, I believe that by stimulating the immune system on a weekly basis with continuous imiquimod therapy, we can suppress the development of precancerous lesions and skin cancer,â€Â Dr. Martin says.

Disclosures: Dr. Martin is a consultant, speaker, and advisory board member at Valeant, DUSA; he is also on the advisory board at LEO and is a consultant for Aqua.

Reference:

1. Martin G. In-office painless aminolevulinic acid photodynamic therapy: a proof of concept study and clinical experience in more than 100 patients. J Clin Aesthet Dermatol. 2016;9(2):19–26.