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New topical agent for actinic keratoses boosts field therapy

Staving off squamous cell carcinoma through the aggressive treatment of actinic keratoses (AKs) can be an uphill battle, as AKs tend to recur on photodamaged skin. Cryotherapy is still the go-to treatment for most dermatologists, accounting for 92 percent of AK treatments administered by U.S. physicians, according to the IMS PharMetrics Integrated Database (a claims database of commercial insurers in the U.S.). Yet several leading dermatologists maintain that particularly for patients with multiple lesions and/or extensive sun damage, field-directed therapy with a topical agent or photodynamic therapy (PDT) should be getting more consideration (see “Attacking actinic keratoses”). “If we just use spot therapy, we’re only treating the tip of the iceberg,” said Stephen K. Tyring, MD, PhD, clinical professor of dermatology at University of Texas Health Sciences Center. “Field therapy reveals a lot of AKs that may be invisible to the clinician’s unaided eye, even if they use a dermatoscope. It’s important to get the subclinical AKs because they may be the ones that are going to lead to a malignancy.” In addition, “the recurrence rate is quite high after a year” with cryotherapy, in contrast with the lower rates of recurrence associated with topical agents. 

Why the reluctance to use field therapy? The factors range from cosmesis to cost, said George Martin, MD, a dermatologist in private practice in Kihei, Hawaii and moderator of a session on field therapy for AKs at Maui Derm 2013. “What matters most to patients is, number one, how much time do I have to take off work, or how much time will it be socially unacceptable for me to appear in public,” he said, noting that both the discomfort and the obvious inflammation associated with topical agents can persist for weeks or months, depending on the specific drug and the regimen. As a result, he said, many patients don’t comply with the therapeutic regimen and some physicians are simply reluctant to prescribe it. Because it’s a procedure, cryotherapy is covered by Medicare (as is PDT), while topical agents may or may not be covered by a patient’s prescription drug plan. [pagebreak]

New drug on the block

Ingenol mebutate, a topical agent approved just last year by the U.S. Food and Drug Administration, is gaining interest among dermatologists because patients apply the gel once daily for only two or three consecutive days. Its efficacy is similar to that of the topical agents previously approved to treat AKs (5-fluorouracil, imiquimod, and diclofenac), Dr. Martin said. In a report on four Phase III studies comparing ingenol mebutate with vehicle, published in the Journal of the American Academy of Dermatology (2013;68(1):S39-48), Dr. Martin and co-author Neil Swanson, MD, found that 42.2 percent of patients treated with ingenol mebutate on the face or scalp achieved complete clearance, and 63.9 percent achieved partial clearance (at least 75 percent of the AKs). Among patients treated on the trunk or extremities, 34.1 percent achieved complete clearance and 49.1 percent achieved partial clearance. Patient compliance in the studies was excellent, Dr. Martin said, “between 98 and 99 percent, because [on the face and scalp], three and done. And on the trunk and extremities, it’s two nights, that simple.”

Patients’ adherence to the regimen is one factor that gives ingenol mebutate “the potential to become a first-line drug,” said Dr. Swanson, who is a professor of dermatology and surgery at Oregon Health and Science University. “In my experience and others’, it has a pretty predictable response that’s similar to the rest: they all make you red, irritated, and ugly during the treatment phase. You’re going to begin to get a reaction within the first couple of days with ingenol mebutate — it peaks between day four and day eight, and it’s gone pretty rapidly after that. If you’re using the others for their FDA-approved regimens — for imiquimod, that’s two weeks on, two weeks off, and for 5-FU it’s at least two weeks on — you’re getting that reaction for the entire period of time you’re putting it on.” As an added bonus, both ingenol mebutate and imiquimod improve the appearance of photoaged skin, Dr. Swanson said.

Another advantage to ingenol mebutate, Dr. Tyring pointed out, is that it “definitely has one of the lowest recurrence rates of any of the topical agents. Of course, we haven’t had the multi-year follow-up that some of the others have, but certainly the first year follow-up studies have demonstrated quite low recurrence rates.” [pagebreak]

Ingenol mebutate is derived from the weed Euphorbia peplus, whose sticky white sap has been used for centuries to treat warts and other skin lesions, including AKs and basal cell carcinoma, according to a JAAD article, co-authored by Dr. Tyring, that describes ingenol mebutate’s mechanism of action (2012;66(3):486-93). Researchers have determined that ingenol mebutate has a dual mechanism of action: rapid lesion necrosis followed by specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. “The exact mechanism is not yet fully determined; there’s still more study that needs to be done with stimulation of the immune system,” Dr. Tyring said. “There are similarities with imiquimod, but we just don’t know the exact cytokines and cellular interactions that occur with ingenol mebutate, as we do with imiquimod.” In their JAAD article, Drs. Martin and Swanson cited research showing that interleukin-8, a neutrophil-attracting cytokine, is produced by rapidly dividing keratinocytes and endothelial cells in response to ingenol mebutate.

While “early adopters have used the drug and really like it,” the cost of ingenol mebutate is a major barrier to more widespread use, Dr. Martin said. “The three-day treatment costs about $700. A tube of 5-FU is less than half of that. And when you figure that the bulk of AK patients are on Medicare, and they’re buying their anti-hypertensives and their diabetic medicines — it’s a hit.” While ingenol mebutate is included in the formularies of some Medicare prescription drug plans, Dr. Swanson noted that “with the other [field therapy] agents, it took a couple of years for them to be reimbursed, so I think it’s going to come for this drug, and I think the price to the patient will end up not too dissimilar.”

Another consideration is that “there’s less comfort in its use because it’s new to the market,” said Abrar Qureshi, MD, assistant professor of dermatology at Harvard Medical School. “Although adherence is better, a lot of prescribing behavior is affected by comfort in prescribing a certain agent. So, physicians are more likely to go to 5-FU or imiquimod because they’ve been using these treatments for awhile.” [pagebreak]

Combinations that work

While Dr. Tyring agreed with Dr. Swanson that the short duration of treatment with ingenol mebutate makes the drug a candidate for first-line therapy, “I don’t think it will be a monotherapy because most dermatologists will continue to use cryotherapy for the most hyperkeratotic AKs and use ingenol mebutate as a supplemental or combination therapy following the cryotherapy.” Alternatively, if initial treatment with ingenol mebutate doesn’t result in complete clearance, dermatologists can use cryotherapy or a less expensive topical agent such as 5-FU to “mop up” remaining AKs, Dr. Martin said. He described a less irritating regimen of 0.5 percent 5-FU that can be used post- ingenol mebutate as an alternative to the traditional four-week treatment cycle: “one week of treatment, then you stop, things peel off, you wait a month then you go for two or three weeks, depending on how much is left and how stubborn it is.”

Dr. Martin emphasized that when it comes to AKs, “no one size fits all,” and treatment can vary by site as well as by patient. On the back of the hands, for example, the area where ingenol mebutate is least efficacious, “some of us use morning 5-FU and night imiquimod, as well as other combinations of agents. Nothing works particularly well for that area as monotherapy; you have to beat the heck out of it to get some response.” In treating a particularly challenging patient — a 70-year-old man with a history of non-melanoma skin cancer — Dr. Martin said he first tried six cycles of PDT with aminolevulinic acid spaced six months apart, followed by one week of 5-FU and one additional PDT session. The patient returned 18 months later “loaded up with AKs again, so I tried imiquimod for a week, then PDT on the eighth day. He was still clear 18 months later. So I’ve concluded that there’s a subgroup of patients where you really need not destructive modalities, but modalities that upregulate the immune system, like imiquimod.” [pagebreak]

PDT may be preferable to topical agents “in patients with severe photodamage and patients for whom appearance is an issue,” Dr. Qureshi said. He noted that patients may be hesitant to use a topical because they flare after each use, adding that “most of the patients we’re treating are elderly, they’re on a number of other medications and have other health issues going on, and often they just don’t want to rock the boat and do yet another treatment that’s going to make them look worse.” In addition, he pointed out, patients sometimes have trouble following instructions for the application of topicals, whereas the physician can control the delivery of PDT.

Field therapy has an important role to play in disease modification and prevention, Dr. Qureshi said, admitting that the approach is somewhat controversial. “The idea is that in patients who have a high burden of AKs or need frequent treatments, there almost needs to be a clinical guideline to treat patients with field therapy as opposed to treating them with cryotherapy,” he said. “As responsible practitioners, we should be treating these patients with immunomodulatory agents to prevent AK development. With the rising cost of care, this may be something we need to do.” Ongoing trials should, within the next year, yield data that tell researchers whether treatment with topical agents or PDT have a protective effect, Dr. Qureshi said, “and if we do see any evidence that it reduces cancer rates in the future, then it’s even more compelling.”

Editor’s note: Dr. Martin is an advisor for Abbott Laboratories, Astellas Pharma Inc., DUSA Pharmaceuticals Inc., Galderma, Graceway Pharmaceuticals LLC, LEO Pharma Inc., Medicis Pharmaceutical Corp., Photocure, and Sanofi; a consultant for DUSA Pharmaceuticals Inc., LEO Pharma Inc., Medicis Pharmaceutical Corp., Photocure, and Valeant Pharmaceuticals International Inc.; a speaker for Abbott Laboratories, DUSA Pharmaceuticals Inc., Graceway Pharmaceuticals LLC, LEO Pharma Inc., and Medicis Pharmaceutical Corp.; and an investigator for Photocure.

Dr. Swanson is an advisor, investigator and speaker for LEO Pharma Inc. and a consultant for LEO Pharma Inc. and Medicis Pharmaceutical Corp.

In the past five years, Dr. Tyring has received grants and honoraria for his work on behalf of GlaxoSmithKline, Novartis, Merck, Amgen, Abbott, and Graceway as, variously, a consultant, investigator, and speaker; grants and honoraria from Galderma for his work as an investigator; honoraria from Warner Chilcott for his work as a speaker; grants and honoraria from Astellas, Inhibitex, and Stiefel for his work as a consultant and investigator; and grants from Eli Lilly and Company and LEO Pharma for his work as an investigator.