Conference Coverage

Beyond sunscreen: Skin cancer preventive agents finding a role


 

EXPERT ANALYSIS FROM SUMMER AAD 2019

Sunscreens remain the front-line strategy for preventing skin cancers of all types, but there is a growing array of chemopreventive agents for keratinocyte carcinomas (KCs) that deserves to be considered for selective use in at-risk patients, according to an update at the American Academy of Dermatology summer meeting.

Dr. Rebecca Hartman, Director of Melanoma Epidemiology, Brigham and Women’s Hospital, Boston

Dr. Rebecca Hartman

In providing her perspective on the available options, Rebecca Hartman, MD, MPH, director of melanoma epidemiology at Brigham and Women’s Hospital, Boston, emphasized that the therapies are not interchangeable but deserve to be used selectively according to their relative protection and relative risks.

Of oral agents, she characterized two, nicotinamide and acitretin, as “clinic-ready.” Acitretin is “an oldie but goodie,” but there is an important issue of tolerability. In the published studies, 15%-39% of patients withdrew because of adverse events, according to Dr. Hartman, which suggests the need for a motivated patient.

In addition, acitretin can be esterified into etretinate, a teratogen that can persist as long as 3 years after the drug is discontinued, making this drug contraindicated in women of childbearing potential, she noted.

However, most patients in need of prophylaxis for KCs are older, so teratogenicity is not an issue. In her practice, she offers acitretin to patients who are developing three or more KCs per year, as well as in situations of extensive skin damage in which a course of acitretin might provide some degree of clearing.

“When you are faced with the potential of a large number of biopsies, you could start acitretin to see if lesions can be reduced,” Dr. Hartman said .

Prevention of KCs became somewhat more attractive as a routine practice following publication of a phase 3 trial with nicotinamide. In this study, nicotinamide, an over-the-counter water-soluble form of vitamin B3, was associated with significantly reduced nonmelanoma skin cancers, including KCs and actinic keratoses, relative to placebo (N Engl J Med. 2015 Oct 22;373[17]:1618-26). Importantly, there was no greater risk of adverse events relative to placebo.

When assessed individually, the relative reduction in squamous cell carcinomas (SCCs; P = .05) and basal cell carcinomas (P = .12) fell short of statistical significance, but there was a highly significant 13% reduction in actinic keratoses after 12 months (P less than .001). An increase in SCCs was observed after therapy was stopped, which led Dr. Hartman to conclude that nicotinamide must be used on a “use-it-or-lose-it” basis. However, she does routinely offer this option.

“When do I recommend nicotinamide? Any patient with multiple actinic keratoses who wants to get ahead of the game and wants something that is relative safe,” Dr. Hartman explained. She uses the same dosing employed in the study, which was 500 mg twice daily.

There are other options for chemoprevention of KCs, but they are less attractive.

For example, capecitabine is effective, but tolerability is an even greater issue with this agent than it is for acitretin. According to Dr. Hartman, “we use this therapy very rarely and only in select cases.” As an alternative to the 14 days on and 7 days off schedule used for treatment of cancer, capecitabine is sometimes better tolerated in a 7 day on and 7 day off schedule, she said.

Topical 5-fluorouracil with or without calcipotriol is another chemoprevention option for those who can tolerate a skin reaction that lasts several days, Dr. Hartman said. She cited one study that associated this therapy with a nearly 80% reduction in face and scalp SCC.

Ultimately, she offers 5-fluorouracil with or without calcipotriol to “patients who want an evidence-based chemoprevention,” but she indicated that patients must be motivated to endure the adverse effects.

Many remain unaware of the array of options for chemoprevention of KCs, but Dr. Hartman emphasized that this is an area of active research with new options expected.

“I am really excited about the future direction of chemoprevention in skin cancer,” said Dr. Hartman, citing ongoing work to develop vitamin A, polypodium leucotomas extract, and human papillomavirus vaccine as options.

“If we can stop skin cancer in the first place, avoiding the morbidity and mortality of treatment, we will also hopefully save costs as well,” she commented. So far, essentially all of the strategies for chemoprevention, other than sunscreen, involve KCs, which leaves a large unmet need for better ways to prevent melanoma. However, Dr. Hartman noted that KCs represent the most common type of cancer of any type.

Just days after Dr. Hartman spoke at the meeting, a prospective study of vitamin A that found an inverse association between vitamin A intake and cutaneous SCC risk was, in fact, published in JAMA Dermatology (2019 Jul 31. doi: 10.1001/jamadermatol.2019.1937).

Dr. Hartman reported no financial relationships relevant to her presentation.

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