Attacking actinic keratoses
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Multiple modalities let dermatologists tailor treatment to the patient

As the second most common diagnosis made by dermatologists (after acne vulgaris), actinic keratosis (AK) is a condition virtually every practicing dermatologist will encounter frequently. Yet despite its prevalence, a number of questions about the condition and its treatment remain unresolved. What percentage of Americans will develop AKs? Is AK a precursor to non-melanoma skin cancer, or is it a malignancy in the earliest stages? What are the optimal treatment strategies? Is it ever appropriate to leave an AK lesion untreated?

“This is a huge health care problem in the U.S. We just don’t have enough data to understand how big a problem it is,” said Abrar Qureshi, MD, MPH, assistant professor of dermatology at Harvard Medical School. An estimate from 2005’s Burden of Skin Diseases report, prepared by The Lewin Group for the American Academy of Dermatology Association and the Society for Investigative Dermatology, put the age-adjusted prevalence for AK in the U.S. at 6.5 percent but noted that “AKs are very common among adults ages 60 to 69, with 83 percent of men and 64 percent of women having at least one lesion.”

Also in question is the rate at which AKs progress to invasive squamous cell carcinoma (SCC). A Journal of the American Academy of Dermatology study examining the dermatoscopic features of AK (in press; see sidebar) found that published estimates of the risk of progression of AK to invasive SCC for individual lesions ranged from 0.1 percent to 20 percent.

Is it cancer?

The lack of data regarding AK extends to the issue of whether AKs are precursor lesions or early malignancies, Dr. Qureshi said. “The data is not clear on the level of risk involved with leaving some AKs untreated. Some associated risk has been proven, but we haven’t quantified that risk.” A common method of assessing the risk is to conduct retrospective reviews of the records of patients with AKs who went on to develop skin cancer. However, Dr. Qureshi pointed out that “people who get treated for AKs, which result from sun damage, are people who are likely to get skin cancer anyway. The question is, how many of the cancers that arose were AKs first?” Dr. Qureshi said he considers AKs to be premalignant, “but there is a school of thought out there among dermatopathologists and dermatologists that AKs are cancer. It’s a very fine line.”

Two dermatologists who addressed the controversy in Cutis (2011;87(4):201-7) concluded that there is insufficient evidence to support the concept that AK is frank squamous cell carcinoma (SCC). However, the authors maintained that the risk for progression of AK to invasive SCC provides the rationale for treatment, an approach recommended by several dermatologists with expertise in treating non-melanoma skin cancer. “I think the bottom line is that it’s largely a semantic difference,” said Steven R. Feldman, MD, PhD, professor of dermatology, pathology, and public health sciences at Wake Forest University School of Medicine and a co-author of the Cutis study. “You can call them skin cancers in an early stage or you can call them pre-cancerous lesions. Either way, they should be treated.” [pagebreak]

Lesion-directed vs. field treatment

Another area under question is the appropriate way to treat AKs. With a broad range of modalities available, dermatologists need to consider not just their own preferences but also those of the patient, experts say. “We don’t have a great treatment that does everything we want it to do,” said Mary E. Maloney, MD, chief of the division of dermatology at the University of Massachusetts Medical School. “We need to be creative and use all of our modalities to try to fit them to the patient rather than fit the patient to our favorite modality.” In addition to the number, features, and location of the AK lesions, factors such as the patient’s age, history of sun exposure, prior AKs, prior skin cancer, and immunosuppression help shape the treatment plan. Economic considerations can also have an impact, both in terms of cost to the patient and reimbursement for the physician.

Dermatologists first must determine whether the treatment regimen will involve destruction of AK lesions as they arise (lesion-directed or “spot” therapy), treatment of a broader field of disease with topical agents or photodynamic therapy (PDT), or a combination of both approaches. Cryotherapy with liquid nitrogen is the most common destructive therapy, although electrodessiccation and curettage is sometimes used to treat thick, hyperkeratotic AKs. Topical agents commonly used for field therapy include 5-fluorouracil (5-FU), imiquimod, and diclofenac gel. Both approaches have proven effective in achieving at least temporary clearance of AKs, and both involve some discomfort, redness, and blistering at the treatment site.

“I think the treatment of AK is somewhat problematic in that there are lots of ways to skin a cat, and lots of compliance issues,” Dr. Maloney said. “It’s absolutely easiest for patients to come in, have a liquid nitrogen treatment, and go home and not have to do anything else. As we move away from that modality, success is much more dependent on a patient being compliant with the treatment regimens. It’s totally ineffective if the patient doesn’t do it.” Other dermatologists point to the belief that field treatment attacks subclinical AKs and may reduce the need for future therapy. “With spot therapy, in my opinion, you’re chasing your tail,” Dr. Qureshi said. “It’s perfectly reasonable to destroy isolated lesions. But I’m talking about the patient who’s had multiple AKs and multiple freezings, had severe dermatoheliosis. You can keep destroying these lesions for months or years. I feel there are patients who are getting spot therapy who should be getting field therapy.”[pagebreak]

Cryotherapy a mainstay

The popularity of cryotherapy for AKs among dermatologists was demonstrated in a study co-authored by Dr. Feldman and published in the Journal of Dermatological Treatment (2006;17(3):162-166). The authors examined the records of 1,743 patients treated for AK and surveyed 293 dermatologists and 241 non-dermatologist physicians who treat AK. Nearly three-quarters of the patients received cryotherapy only, while 16 percent received topical therapy only, and fewer than 10 percent received both treatments. Dermatologists were three times more likely to use cryotherapy than non-dermatologists.

“Patients in the study indicated a preference for drug treatment rather than cryotherapy, although in real life, when they see the cost of the drug they often opt for the procedure,” Dr. Feldman said. The physician reimbursement structure favors the office-based procedure, and many patients’ insurance policies make the cryotherapy procedure less costly than a course of drug treatment, Dr. Feldman said. “I want to give my patients the best care, irrespective of what I’m being paid. And the real issue that comes up in my practice is that I will think it’s in the patient’s best interest to have a topical therapy for many thin lesions, and they will come back and say no, go ahead and do the procedure because the cream costs too much.”

The experts were in broad agreement that cryotherapy is most appropriate for fewer lesions and those that are particularly thick or hyperkeratotic. Short-term effects can include blistering and redness; longer term, hypopigmentation may occur. “It’s very time-efficient and cost-efficient for the dermatologist, but it’s only treating the visible lesions and it’s not a 100 percent cure; there can be persistence or a recurrence at the treatment site,” said James Q. Del Rosso, DO, dermatology residency program director at Valley Hospital Medical Center in Las Vegas, and a private practitioner of dermatology and dermatologic surgery at Las Vegas Skin and Cancer Clinics. “A lot of factors affect the outcomes after cryotherapy: how long you spray the liquid nitrogen, how far away the spray tip is held from the lesion, the caliber of the tip used, and how much is being delivered. The longer you spray it, the more reaction you’re going to get, and the more likely you are to get more severe blistering or complications such as hypopigmentation.” Dr. Maloney concurred, remarking that the success of cryotherapy depends on “if you’re willing to freeze vigorously. A very light freeze may not be terribly effective. With a very vigorous double freeze-thaw cycle, success is much better, but one must recognize the increased risk for erosion and scar with the more vigorous freeze.” [pagebreak]

Topical therapies, PDT provide options

For patients with multiple AKs and extensive sun damage, field treatment with a topical agent or PDT may be the most cost-effective and efficacious approach to therapy. The oldest topical remedy for AKs still in use, 5-FU prevents cell proliferation and leads to selective cell death. Imiquimod, approved by the U.S. Food and Drug Administration in 1997, activates immune cells through the toll-like receptor 7. Diclofenac gel is a nonsteroidal anti-inflammatory drug, approved by the FDA in 2000. It selectively inhibits cyclooxygenase and potentially acts through the induction of apoptosis, inhibition of angiogenesis, and up-regulation of the arachidonic pathway, according to a study of its therapeutic potential in the International Journal of Dermatology (2001;40(11):709-713).

When faced with a choice among the topical agents, patients often express a preference based on the length of the course of treatment, level of discomfort, and the appearance of their skin, dermatologists said. “The 5-FU almost always causes a vigorous reaction, and patients usually do not prefer to use it on the face,” said Dr. Qureshi. “You use it once or twice a day for about two weeks. Typically, it’s cheaper to use on large body areas like the chest, arms, and back. And then on the face, I’ll often use imiquimod at once-a-week frequency so they get the benefit without the reaction you don’t get that redness and crusting at once a week. But, the duration of treatment is 12 to 16 weeks.” A newer formulation of imiquimod may provide a treatment regimen that is easier for patients to follow, according to William Huang, MD, MPH, assistant professor of dermatology at Wake Forest University School of Medicine. “The original formulation of imiquimod was a 5 percent cream that was FDA approved to treat actinic keratoses when used twice a week for 16 weeks. This prolonged course can lead to challenges in patient adherence to the medication in addition to the discomfort of the treatment itself. A newer 3.75 percent cream formulation of imiquimod has a somewhat easier regimen to follow. The medication is used nightly for two weeks, then off the medication for two weeks, then on again nightly for two weeks. Many patients find this a more convenient dosing schedule.”

Dr. Del Rosso said that although many physicians prefer 5-FU because they have more experience with it, both imiquimod and diclofenac gel “appear to have greater long-term benefit in clearing AKs in many patients as compared to 5-FU, based on the data that is available thus far.” A long-term follow-up study of diclofenac sodium 3 percent gel treatment, published in the Journal of Clinical Aesthetic Dermatology (2009;2(7):20-5), found that one year after treatment of AK lesions, 79 percent of patients had 100 percent clearance of target lesions, and 91 percent of patients had 75 percent clearance of target lesions. A randomized study comparing three AK treatments, published in the British Journal of Dermatology (2007;157 Suppl 2:34-40), found that after one year, the sustained clearance rate of initially cleared individual lesions was 28 percent for cryosurgery, 54 percent for 5-FU, and 73 percent for imiquimod.

“Imiquimod has proven, sustained, long-term benefit in terms of reducing the number of lesions both the initial lesions that were there in the beginning and new lesions developing in the field of treatment,” Dr. Del Rosso said. “Diclofenac gel also has some proven sustained benefit in the area of treatment. The longer recommended treatment course with topical diclofenac is twice daily application for three months, but the amount of visible redness and inflammation is, in the majority of patients, significantly less. Most of these patients don’t have any downtime, they just have to treat over a longer period of time.”[pagebreak]

A third topical agent, ingenol mebutate gel, is currently in Phase III testing for the treatment of AK lesions. Derived from the sap of the plant Euphorbia peplus, the treatment regimen is only two or three days. A study published by a group of Australian physicians in JAAD (2011;Nov 4 Epub) suggested a dual mechanism of action: rapid lesion necrosis and specific neutrophil-mediated, antibody-dependent cellular toxicity. “Reaction occurs over a period of a week to a couple of weeks,” said Dr. Del Rosso, who was not an investigator in the clinical studies of ingenol mebutate, but has reviewed results and photographs from several of the studies evaluating this agent for treatment of AKs. “Some discomfort and some inflammation is to be expected at least in some patients, although most appear to tolerate the therapy well. It’s been studied in a variety of locations: face, scalp, trunk, and extremities.”

Photodynamic therapy for AK can be conducted with either 5-aminolevunlinic acid (ALA) plus blue light, or methyl-ALA plus red light. Daniel Pearce, MD, assistant professor of dermatololgy at Wake Forest University School of Medicine, is using blue light PDT on a trial basis. “One thing I’ve seen in my practice this past year is that folks will come in with a desire to do something different,” he said. “They’ve tried all the topicals, they all have decent efficacies, but anyone with a chronic, visible disease is always looking for something better.” One distinct advantage is compliance, Dr. Pearce said. “I really like the idea that they come in, they get incubated, they’re treated. You don’t have to depend on them to put something on their sore, weeping face for the next two weeks.” A disadvantage to patients is time spent in the office: 60 to 90 minutes for incubation plus the 16-minute treatment. “Also, you have to avoid all UV light exposure for 48 hours after treatment, and that’s a difficulty for people. You can’t just use sunscreen,” Dr. Pearce said. Although long-term studies have not compared the clearance rate for PDT with those of topical agents, Dr. Pearce said the clearance rate after a course of treatment (two PDT treatments three weeks apart) is comparable to that of other modalities. (See "New research" sidebar for research on new techniques for treating AK with PDT.)

Best of both worlds

For many patients, the optimal approach to treatment involves both lesion-directed and field-based therapy. Sequential therapy with cryosurgery followed by PDT is “a great way to go,” Dr. Pearce said. “Because PDT doesn’t do especially well with the thicker spots, you may choose to ablate them at your first evaluation with the cryosurgery, and then you leave the more subtle, lower-grade AKs for the field-based treatment at a later date with the PDT.” Dr. Qureshi takes a similar approach in following cryotherapy with a topical agent, in the belief that “a combination of therapies is probably the best strategy to get your patients clear and prevent cancer.”

New research on the diagnosis and treatment of actinic keratoses

Recently published research examines the dermoscopic features of non-melanoma skin cancer and highlights new techniques in the use of photodynamic therapy (PDT) to treat actinic keratosis (AK).

Noting that the differentiation of early AK lesions on clinical grounds alone can be difficult, a group of physicians from Austria, Australia, and Italy sought to elaborate dermoscopic features that can help distinguish AK, intraepidermal carcinoma (IEC), and invasive squamous cell carcinoma (SCC). Their analysis of 243 tumors, published in the Journal of the American Academy of Dermatology (in press), found that the majority of facial AKs exhibited a red pseudonetwork (“strawberry”) pattern. This pseudonetwork was rarely seen in IEC and invasive SCC lesions, which tended to show increased vascularity and signs of keratinization. The authors propose, describe, and illustrate a progression model of facial AK developing into IEC and invasive SCC, and hypothesize that dermoscopy reveals a red starburst pattern in lesions undergoing a dynamic period of progression.

Several investigators are exploring the combination of two treatment modalities for AK, together or in sequence, in search of a synergistic effect. In a study published in the Journal of Drugs in Dermatology (2011;10(10):1124-1132), Barry Galitzer, MD, tested the effect of pretreatment with tazarotene cream on the outcomes of 10 patients treated with PDT for AK lesions of the hand and forearm. One dorsal hand or forearm was pretreated with tazarotene gel 0.1 percent twice a day for one week before irradiation with blue light PDT; the other hand or arm was not pretreated. Lesion counts on the treatment area at baseline and eight weeks following treatment suggested that pretreatment with tazarotene may have slightly enhanced the efficacy of the PDT. Tolerability was similar between the two groups except for significantly more erythema in the tazarotene-treated arm five minutes after PDT.

A group of 31 researchers tested the safety and efficacy of a new formulation of 5-aminolevulinic acid (ALA) in PDT. The new agent, BF-200 ALA, is a gel formulation with nanoemulsion which overcomes previous problems of ALA instability and improves skin penetration. Results of the phase III study, a randomized trial of 600 patients, will be published in the British Journal of Dermatology. Compared with a registered methyl-ALA cream (MAL) and placebo, the patient complete clearance rates 12 weeks after the last PDT were 78.2 percent for BF-200 ALA, 64.2 percent for MAL, and 17.1 percent for placebo.



New research on the diagnosis and treatment of actinic keratoses