LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with , with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
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Dr. Kishwer S. Nehal
The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.
The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.
The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.
Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.
“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.
While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.
“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.
Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.
“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”
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Dr. Paul Nghiem
He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.
“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.
Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).
“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”
Session chair Ashfaq A. Marghoob, MD, is of a similar mind.
“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).
Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.
“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”
“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.
Dr. Nehal reported having no conflicts of interest regarding her presentation.
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