Medical Management of Actinic Keratoses and Non- Melanoma Skin Cancer: Disease Progression and Mechanisms of Action of Therapy

Recent reviews assess how new therapies for actinic keratoses (AKs) can effectively treat clinical and subclinical lesions with adequate tolerability. Many of our colleagues in dermatology are still of the mindset that AKs either don't need treatment, need destruction alone, or that topical therapies are not worth the price that many patients have to bear (not remembering that development of squamous cell carcinoma [SCC] is an entirely different price to pay; Figure 1).

A prevailing impediment to adding topical management is truly understanding the disease state that is being treated. Actinic keratoses are a reflection of unprotected sun exposure from years, not days, almost like an investment in time of pathogenesis, with a consequence of skin cancer. Therefore, we can describe AKs as a “symptom” of the “disease” of photodamage with SCC as an “endpoint” of that disease, which in many ways can help place medical management into its context.1-3 Indicators of progression from an AK to SCC include the dysregulation of p53— uncontrolled cell proliferation; expression of p16 oncogene; and the inducible expression of Fas (CD 95) ligand. The progression of carcinogenesis can be found in Figure 2.

In many ways, we should treat AKs like we treat acne. We don't just use spot treatment such as clindamycin solution. We use retinoids to treat the keratinization defect, benzoyl peroxide to treat bacterial load and inflammation, and systemic antibiotics to control inflammation—all of which are attempting to impact the disease process, not just the symptoms.

With that in mind, the appearance of multiple AKs in a field should signal that the entire area is photodamaged. Therefore, the goal of field therapy is not only to treat clinical lesions (what we see), but also to reveal and destroy the AKs that are not visible before the start of treatment (what is on the way). More importantly, aggressive field therapy should even attempt to restore local immune mechanisms to restore and repair the effects of photodamage. This includes counteracting reactive oxygen species, maximizing wound healing, and most importantly, restoring tumor surveillance and antigen presentation to stop “disease” progression, rather than just treating the “symptoms.”

Clinicians should be prepared to discuss with patients the reality of medical therapy for AKs, but a fundamental understanding of mechanisms of action is also important. Table 1 shows how some popular therapy options work.^4-6 In particular, recent updates on the mechanism of action of diclofenac sodium from an immunohistochemical analysis show a decrease in expression of COX-2, CD3, and CD8; clear reduction of CD31 expression as a marker for angiogenetic processes; and reduction in markers for proliferation and apoptosis. ⁷ Additionally, Table 2 reveals the statistical evaluation of immunohistochemical parameters before and after AK treatment compared to untreated healthy control skin.⁷ The markers listed are indicators of how these therapies impact the entire disease process as it relates to photodamage.

Chemoprevention in NMSC

Specifically, there are risk factors for non-melanoma skin cancer (NMSC) in organ transplant recipients (OTR), which include age, skin type, sun exposure, and history of prior NMSC. When these factors combine, immunosuppression levels are directly related to NMSC incidence.^8,9

There are two primary systemic strategies when considering chemoprevention for patients with NMSC: oral retinoids or the reduction of immunosuppression. In high-risk patients, the benefits of systemic chemoprevention outweigh the adverse effects.^10,11 Although systemic chemoprevention can augment surgical therapy, it does not completely replace it. Dermatologists must balance morbidity, the inconvenience of surgery, and the risk of progression with the adverse effects of systemic therapy.

The introduction of low-dose acitretin proved to be a useful strategy in the long-term reduction of skin cancer and the occurrence of keratotic skin lesions in a group of renal transplant recipients with severe lesions. This effect was most pronounced in patients with a history of squamous cell carcinomas and basal cell carcinomas.^12,13

Polypodium leucotomos (HeliocareTM) is a botanical antioxidant supplement that has demonstrated reduction in the damage induced by cumulative UVB exposure.¹⁴ The mechanisms of action include direct photon absorption, inhibition of glutathione oxidation, and reduction of the UV-induced depletion of Langerhans cells. Over time, there is improvement in erythema and atypical epidermal hyperplasia—important components in the progression from photodamage into neoplasia.¹⁵ However, there is currently no indication for Polypodium leucotomos as a chemoprevention agent.

Future topical chemoprevention agents include topical colchicine 1% gel; EGOC, a polyphenol derivative and pro IL-12; perillyl alcohol, a citrus-peel derived cream; difluoromethylornithine 10% ointment, which showed a 23.5 percent reduction in the number of AKs after 6 months¹⁶; silymarin, a milk thistle plant; and T4 endonuclease V, a pro IL-10.

Topical chemoprevention for AKs also includes the use of eflornithine with or without triamcinolone, which is currently undergoing Phase 2 study.¹⁷ The trial researchers seek to compare the safety and efficacy of eflornithine versus placebo as chemoprevention of NMSC in patients with moderate to heavy AK; determine whether this drug reverses AK in these patients; and determine whether triamcinolone reduces their eflornithine-induced skin irritation. It appears the utility of chemoprevention will always be off-label and up to us as physicians to decide the best course for treatment.

Managing Expectations

Patients should expect to experience some degree of irritation and inflammation with any topical AK therapy, such as imiquimod or ingenol mebutate. Even if discomfort is minimal, erythema may develop, and swelling, significant erythema, and crusting are all possible. However, there might also be a group of patients that do not have vigorous responses and be considered “treatment failures.” The take-home caveat to successful use of topical therapy is that the endpoint of treatment should be much more significant to the clinician than the reaction, meaning that the lesion count is the measure of success and not the erythema that is experienced.

Avoidance of sun exposure and faithful use of sunscreens during the treatment phase is essential and serves as a good preparation for a future of sun-safety practices (Table 3). Patients should understand the similarities and differences between treatment options. Additionally, gentle skin care, bland moisturizers, and even cold compresses can be used to reduce the degree of therapy-induced irritation. In the event of significant inflammation, topical corticosteroids may be used to calm the response.

Adequate patient follow-up is essential to successful medical management of AKs with check-up appointments scheduled at appropriate intervals. Patients must be encouraged to call with any questions or concerns. Some practices have even implemented “walk-in” privileges for all medically managed AK patients so that they can receive immediate evaluation of any application site reaction. In any case, the best way to avoid phone calls and potential complaints is to schedule a brief follow-up visit to review the reactions in person and help manage expectations.

The Pharmacist's Role

Given the prescriber's expertise in selecting a medical treatment and dosing regimen for AKs that will optimize efficacy and tolerability, it is important that patients receive the prescribed intervention. Pharmacists can play a crucial role in supporting medical therapy of AKs or, unfortunately, in inhibiting therapeutic success. The issue of inappropriate substitution is a problem across dermatology but can be particularly challenging in the management of AK.

When pharmacies substitute—or, as sometimes happens, when they inappropriately change the prescription— vigorous responses may occur that are not anticipated by the patient or the dermatologist. As a result, patients often stop the drug, leading to non-compliance, or end up with extreme reactions that lead to upset phone calls, visits to the emergency room, or significant consequences.

New Directions in Management

Medical management of AKs is a logical and increasingly important approach to patient care. Medical therapy targets visible lesions as well as preclinical lesions and other symptoms of chronic photodamage. It may be more convenient and by providing a field effect potentially provides better long-term outcomes than destructive modalities. The clinician must select the medical treatment likely to provide greatest efficacy with optimal tolerability. Patient education and counseling are essential to a positive patient experience. Advise patients of the therapy selected, strategies for enhancing tolerability, and the importance of checking their prescription to avoid inappropriate substitution.

Neal Bhatia, MD is in practice at Laser Skin Care Center Dermatology Associates in Long Beach, CA and is Associate Professor of Dermatology at Harbor UCLA

Dr. Bhatia has affiliations with Bayer, Ferndale, Galderma, Genentech, Leo, Medicis, Onset, PharmaDerm, Promius, Quinnova, and Valeant.

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