Which Actinic Keratosis Treatment Works Best? Reading the Head to Head Trial

If you have several rough, scaly actinic keratosis spots on your scalp or forehead and you want the treatment most likely to still be working a year from now, the best current head to head evidence points to one answer: 5 percent fluorouracil cream. When researchers put four common field therapies against each other in a single randomized trial, fluorouracil cleared roughly three out of four patients at 12 months, and no competing option came close.

Key points#

• A 2019 New England Journal of Medicine trial randomly assigned 624 patients to one of four field therapies for actinic keratosis on the head.
• At 12 months, 5 percent fluorouracil cream reached the success target in about 75 percent of patients, well ahead of imiquimod, photodynamic therapy, and ingenol mebutate.
• Every rival carried a significantly higher risk of treatment failure, with confidence intervals that never touched the line of no effect.
• Fluorouracil's advantage comes with more skin irritation during the course, a trade-off worth discussing.
• The worst performer, ingenol mebutate, was later pulled from the European market over a skin cancer signal.

Why treat the whole patch, not just the spots#

To make sense of the trial, it helps to start with the idea it was designed to test. Actinic keratoses are the visible signs of long-term sun damage, but the damage is rarely limited to the bumps you can feel. Years of ultraviolet light alter a broad zone of skin, planting genetic changes in cells that still look ordinary. Dermatologists call this field cancerization. The rough spot you notice is the tip of a much larger area of altered skin, and unseen lesions sit hidden beside it.

That is the argument for field therapy. Freezing or scraping the individual spots you can see, called lesion-directed treatment, leaves the surrounding zone untouched, which is why new lesions so often crop up nearby within months. Field therapy instead treats the whole affected patch with a cream, gel, or light-activated agent, aiming to reach the subclinical damage as well as the obvious lesions. Think of it as reseeding an entire weathered lawn rather than pulling one weed at a time.

How the trial was built#

The study, led by Jansen and colleagues and published in 2019, enrolled patients at four Dutch hospitals between late 2014 and early 2017. To qualify, a person needed at least five actinic keratosis lesions clustered within one continuous area of 25 to 100 square centimeters on the head. Each of the 624 participants was randomly assigned to one of four field-directed treatments:

• 5 percent fluorouracil cream
• 5 percent imiquimod cream
• methyl aminolevulinate photodynamic therapy (MAL-PDT)
• 0.015 percent ingenol mebutate gel

The outcome the researchers cared about was strict and practical: the share of patients who reached a reduction of 75 percent or more in their lesion count, measured from the start to a full 12 months after treatment ended. That one-year checkpoint is the design's understated strength. Many skin studies declare victory a few weeks out, when almost any agent that inflames and peels the skin looks like a success. Waiting twelve months tells apart lasting clearance from a temporary flush that fades.

The ranking at one year#

Judged by that tougher standard, the four arms pulled apart. Fluorouracil succeeded in 74.7 percent of patients (95 percent confidence interval, 66.8 to 81.0). Imiquimod followed at 53.9 percent, MAL-PDT at 37.7 percent, and ingenol mebutate trailed at 28.9 percent. This was not a close race. The top arm cleared roughly two and a half times as many patients as the weakest one.

Making sense of the hazard ratios#

The authors also expressed the comparisons as hazard ratios for treatment failure, each measured against fluorouracil as the reference. A hazard ratio captures relative risk over the follow-up window. A value of 1.0 would mean no difference from fluorouracil, and anything higher means failure arrived more often or sooner.

Set against fluorouracil, the hazard ratio for failure was 2.03 with imiquimod (95 percent confidence interval, 1.36 to 3.04), 2.73 with MAL-PDT (1.87 to 3.99), and 3.33 with ingenol mebutate (2.29 to 4.85). Put plainly, patients on ingenol mebutate were more than three times as likely to reach the failure endpoint as those on fluorouracil. Two things make these numbers convincing rather than noise. Every confidence interval sits entirely above 1.0, so none of the differences is compatible with a tie, and each comparison came with a P value at or below 0.001. Here the size of the effect and the statistical certainty point the same way.

The honest trade-off#

None of this makes fluorouracil painless. Its advantage comes with a tolerability cost: it tends to cause stronger local skin reactions during the treatment course, including redness, crusting, and irritation. Some people find a demanding weeks-long cream harder to finish than a shorter regimen. The trial's headline was durable results at one year, and that discomfort is a real part of any honest weighing of options, especially for someone who struggles to stick with a course that visibly irritates the skin.

The footnote that sharpened the message#

The trial came with an unexpected postscript. Ingenol mebutate, the weakest of the four arms, is no longer an approved product in Europe. In early 2020 the European Medicines Agency reviewed its safety after data suggested a higher number of skin cancers in treated areas. In April 2020 the agency concluded that its risks outweighed its benefits, pointing to an increased occurrence of skin cancer, particularly squamous cell carcinoma, compared with imiquimod-treated skin. Its marketing authorization had already been suspended and then withdrawn earlier that year.

So the arm that did worst on lasting clearance also carried the least reassuring safety profile. It is a tidy reminder that the option marketed as fastest and most convenient is not automatically the one that serves a patient best over time.

What this evidence does and does not settle#

Read carefully, the trial makes a specific, bounded claim: among these four field therapies, at these strengths, for multiple actinic keratoses on the head, fluorouracil delivered the most durable clearance at one year. It does not crown a single treatment for every body site, every lesion grade, or every person who cannot tolerate a harsh topical course. A single well-run trial is strong evidence, not the entire literature, and site differences, cost, skin tone, and tolerability all shape a real decision.

What the data do give is a clear anchor. When one option doubles the lasting response of another and the confidence intervals never cross the line of no effect, the signal deserves to be taken seriously.