Evolving Landscape of Therapeutics for Actinic Keratoses (AKs)

George Martin, MD

At the podium during Maui Derm 2011, I discussed the evolving landscape of therapeutics for actinic keratoses (AKs).  In the US nearly 60% of “at risk” individuals over the age of 40 have at least 1 AK.  Therapy for AKs has resulted in over 5 million office visits with an estimated healthcare burden of over 1 billion dollars.

As healthcare initiatives examine and reward patient therapeutic “outcomes”, the clear lack of efficacy of cryosurgery as a “field therapy” for patients with numerous AKs will cause a shift in therapeutic algorithms toward field therapies.  However; field therapies, when performed according to the package insert, are associated with prolonged side effects that dramatically affect patient compliance.  As a result, small investigator initiated studies examining short course, combination and interval therapy in efforts to enhance patient compliance while maintaining efficacy are becoming more prevalent in the literature. Additionally new drugs such as the plant derived ingenol mebutate gel are ready to be brought to the marketplace and new formulations of existing drugs such as imiquimod 3.75%, which employs a more “user friendly” protocol compared to 16 weeks of twice daily 5% imiquimod, have been introduced.

I presented the work of Prof. Eggert Stockfleth of Charite Hospital in Berlin who has published compelling molecular data on the role of human papilloma virus (HPV) 21 as a co-carcinogen along with UV.  The role of HPV 21 is analogous to the role of certain oncogenic HPV sub-types in cervical cancer.  HPV 21 has been found in 95% of AKs and 100% of cutaneous SCCs in Prof. Stockfleth’s study. Tumour-inducing effects of HPV 21 have been attributed to its production the viral protein E6.  E6 interacts with pro-apoptotic Bak-protein and the p53 protein resulting in inhibition of apoptosis.   A vaccine directed against the HPV 21 is in early stages of development. Because of the increased risk of SCC development in organ transplant patients  (>20x the rate of SCC development compared to non-immunocompromised individuals) the efficacy of pre-operative immunization in preventing AKs and SCC in this high-risk group will be studied first.

ALA PDT has come a long way from its lengthy 14 – 18 hr. incubation times in efforts to become user friendly.  However, I presented data that the shorter 1-hour ALA incubation times may have sacrificed significant efficacy for convenience.  Based on fluorokinetic data on the accumulation of the photosensitizer protoporphyrin IX (PpIX) inside AKs following ALA application (Figure 1) and patient observation, we now regularly treat patients using a minimum of 3-hour ALA incubation period to allow more PpIX accumulation inside AKs.  In patients with “stubborn” AKs we pre-treat with 5-FU daily for 7 days on the face and 10 days on the scalp and extremities followed by PDT using 1 – 3 hour incubations.  Lastly, for the patient with extensive AKs on the face and scalp who I never seem to get close to clearing, pretreating with 3.75% imiquimod for 1 week followed by ALA PDT using a 3 hour incubation has produced remarkable sustained clearance not achieved in either ALA PDT alone or in combination with 5-FU.

I addressed the issue of pharmaco-economics involving our currently available field therapies.   Medicare insurance covers the cost of ALA PDT, which is a decision factor for cash strapped seniors unable to afford the several hundreds of dollars for topical field therapies.   In terms of downtime for working individuals, ALA PDT affords the least amount of downtime (generally 1 week) compared to other field therapies (Figure 2).

5-FU remains a cornerstone of  field therapy in most our practices.  I was noted that phase III data on 0.5% 5-FU showed that 1 week of daily use of 0.5% 5-FU cleared nearly 75% of individual AKs.    I think that it is time that we should re-examine the scorched earth policy of 4-week 5-FU therapy!

What’s been overlooked for actinic chelitis?   3% diclofenac gel applied twice daily for 3 months is particularly effective for this problem. It is very tolerated and results in excellent clearance data with over 80% of individual lesions clearing and patient satisfaction was rated as very high.  (Figure 3) For those patients not wishing at least 2 weeks of downtime following any of the current modalities ranging from PDT, CO2 laser resurfacing, 5-FU or imiquimod this is a tolerable option that allows people to continue socializing.  Recent data on 3% diclofenac has shown significant long-term clearance during the phase IV study involving 1-year follow-up evaluations.

The evolution of imiquimod therapy for the treatment of AKs has undergone an evolution since the introduction of 5% imiquimod applied twice weekly for 16 weeks.  While the efficacy of this regimen is significant, the tolerability and patient compliance is wanting.  In Europe the use of 5% imiquimod 3-times weekly 4 weeks followed by a 4-week rest period and repeated produces excellent clinical and histologic clearance long term (1 year) clearance but is once again associated with significant patient downtime.  Limiting therapy to only 4 weeks results in only <30% clearance compared to two cycles that result in approximately an 85% clearance.  The introduction of 3.75% imiquimod applied daily for 2 weeks-2 weeks off- 2 weeks on has resulted in better patient tolerance and impressive individual lesion clearance (>80%). Long-term complete clearance (1 year) data for those phase III study patients initially completely clearing was 40%. In light of the role of HPV 21 as a co-carcinogen responsible for the development of AKs and cutaneous SCCs, the use of imiquimod as an immune modulator used either alone or in combination would seem to have a therapeutic advantage.

Finally, ingenol mebutate 0.015% gel when applied for 3 consecutive days during phase III studies, produced very nice and consistent clearance data (80% range) as a field therapy for the head area (face and scalp).  The 3-day topical therapy had excellent patient compliance, which is a major challenge for other field therapies.  Downtime following ingenol mebutate was on average 2 weeks.  It will be interesting to see how this drug will be used as a field therapy because of the inability to “titrate” its response following application.  Likely most of us will begin using it a “limited area” field therapy. However the future seems very bright for this latest pending addition to our therapeutic toolbox.