American Melanoma Institute · 5 min read
What fluorouracil, imiquimod, tirbanibulin, and diclofenac treat, the skin reaction to expect week by week, and how the options compared in a head-to-head trial.
Some skin precancers and a few thin skin cancers can be treated at home with a prescription cream. A cream involves no cutting, leaves no scar, and treats a whole sun-damaged area at once. The cost is a skin reaction that looks alarming for a few weeks.
Actinic keratoses are rough, scaly patches caused by years of sun. A small share turn into squamous cell carcinoma over time. They rarely come alone. Skin around a visible keratosis carries the same sun damage, and new spots keep surfacing, a pattern doctors call field cancerization.
Freezing treats one spot at a time. A cream covers the whole forehead, scalp, or forearm, and treats the keratoses you can see along with the ones still forming. The 4 drugs below are approved in the United States for actinic keratoses.
Fluorouracil, often written 5-FU, is a chemotherapy drug in cream form. It blocks DNA production, and fast-dividing abnormal cells take up far more of it than normal skin does. The usual course is once or twice a day for 2 to 4 weeks.
The reaction follows a predictable arc. Around days 5 to 10 the treated skin turns red, scaly, and tender, and abnormal spots you never noticed light up. Sores and crusts follow. The skin looks its worst near the end of the course. After the last dose, healthy skin replaces the damaged skin over 2 to 4 weeks, and leftover pinkness can take longer to fade. A strong reaction means the drug found plenty of damaged cells.
A few cautions apply. Fluorouracil can cause birth defects, so pregnant women should not use it. People born with a shortage of an enzyme called DPD can have a severe reaction. Keep the tube away from pets, since swallowing it can kill a dog or cat.
Imiquimod contains no chemotherapy. It switches on a receptor on immune cells in the skin, which then release signaling proteins that draw an immune attack onto abnormal cells. Schedules vary by product: a common one for actinic keratoses is 2 nights a week for 16 weeks, and some versions are used nightly in 2-week cycles with a rest between.
The skin reaction resembles the fluorouracil one: redness, itching, scabbing, sometimes shallow sores. Some people also feel as if they have a mild flu, with fatigue, aches, or headache, which passes within days of stopping.
Tirbanibulin ointment (brand name Klisyri) is the newest option, approved for actinic keratoses on the face or scalp. The whole course is once a day for 5 days. In the 2 trials behind its FDA approval, 44% and 54% of patients had every keratosis in the treated area clear by day 57, compared with 5% and 13% of those using a dummy ointment. Reactions are mostly mild redness and flaking. The short course is its main draw. How long the clearance lasts is less well studied than for fluorouracil.
Diclofenac 3% gel is an anti-inflammatory drug. The schedule is twice a day for 2 to 3 months, and the American Academy of Dermatology notes that it tends to cause less of a skin reaction than fluorouracil. It suits people who cannot tolerate the stronger creams, and it clears fewer keratoses than they do.
Calcipotriene is a vitamin D-based ointment approved for psoriasis. Mixed with fluorouracil, it prompts skin cells to release a signal that recruits T cells against the keratoses. A randomized trial (Cunningham and colleagues, Journal of Clinical Investigation, 2017) tested a 4-day, twice-daily course in 131 participants. The combination reduced the number of actinic keratoses by an average of about 88%, compared with 26% for fluorouracil mixed with plain petrolatum.
The combination is off-label, meaning the FDA has not approved it for this use, and a pharmacy has to mix it or you mix equal parts at home. The reaction is brisk, with redness and burning that peak in the week after the last dose.
One large trial compared field treatments head to head (Jansen and colleagues, New England Journal of Medicine, 2019). It enrolled 624 patients at 4 Dutch hospitals, each with at least 5 actinic keratoses on the head. Treatment counted as successful when at least 75% of the keratoses cleared and stayed clear.
At 12 months after treatment, about 75% of the fluorouracil group remained successfully treated. The figure was 54% for imiquimod, 38% for photodynamic therapy with methyl aminolevulinate, and 29% for ingenol mebutate gel, a product that European regulators later pulled from the market over safety concerns. Tirbanibulin and the calcipotriene combination did not exist as options when the trial was designed, so no one knows where they would rank.
Fluorouracil and imiquimod are both used for superficial basal cell carcinoma, a thin subtype that spreads along the surface. The imiquimod schedule for this use is 5 nights a week for 6 weeks. The Skin Cancer Foundation puts cure rates for these creams between 80% and 90%, lower than surgery, and warns that a tumor called superficial on biopsy sometimes hides a deeper portion elsewhere in the same lesion.
Doctors therefore reserve creams for small superficial basal cell carcinomas on the trunk and limbs, usually in people for whom surgery is a poor fit. Dermatologists also prescribe them off-label for squamous cell carcinoma in situ. A cream is the wrong tool for nodular or infiltrative basal cell carcinoma, invasive squamous cell carcinoma, and melanoma. The treated site needs a follow-up look a few months later, since a cream leaves no pathology report to confirm the tumor is gone.
