What’s the Best Treatment for Actinic Keratosis?

Paul is a 65-year-old man who has spent much of his life enjoying the outdoors. He belongs to a local surf club and continues to swim outdoors on a regular basis. Over the last 10 years, Paul has been treated for various sun spots, including surgical removal of a small squamous cell carcinoma from his left ear. He was evaluated by his dermatologist for multiple new lesions on the dorsal aspect of his right arm and diagnosed with actinic keratosis. What’s the best treatment for Paul?

Actinic keratosis is one of the most common premalignant skin diseases, with a prevalence of 37.5% in white patients aged 50 years and older. Available treatments include cryotherapy for solitary lesions, phototherapy, and topical medications (e.g., fluorouracil cream). However, the guidelines are not clear regarding which treatment is preferred.

In a multicenter, single-blind, randomized, controlled trial recently published in NEJM, Jansen et al. compared the effectiveness of fluorouracil cream, imiquimod cream, ingenol mebutate gel, or methylaminolevulinate photodynamic therapy in patients with a clinical diagnosis of five or more actinic keratoses in a continuous skin area. At 12 months after the end of treatment, 5% fluorouracil cream was the most effective treatment.

The following NEJM Journal Watch summary explains the study:

Patients with actinic keratoses (AKs), which can progress to cutaneous squamous cell carcinoma, often are treated with any of several “field-directed” therapies when they have areas with multiple lesions. In this randomized trial that involved 624 patients, four field-directed alternatives were compared:

• 5% fluorouracil cream (disrupts DNA synthesis)

• 5% imiquimod cream (stimulates local immune response)

• Photodynamic therapy (induces cell necrosis when photosensitizing drug is applied and skin is exposed to light)

• Ingenol mebutate gel (injures mitochondria and plasma membranes)

All participants had at least five AKs on their heads, within an area of 25 cm² to 100 cm². Patients could be retreated if initial response was inadequate. The primary endpoint was at least 75% reduction in number of lesions at 1 year; a dermatologist who was unaware of treatment assignment assessed this outcome. The proportion of patients who achieved the primary endpoint was significantly higher with fluorouracil (75%) than with imiquimod (54%), photodynamic therapy (38%), or ingenol mebutate (29%).

Comment: Each of these field-directed treatments for patients with multiple, closely spaced AKs has some advantages and disadvantages that might influence patients' preferences. However, 5% fluorouracil clearly was the most effective agent in this trial, and its adverse effects profile was similar to those of the other agents. For patients with a few isolated AKs, liquid nitrogen cryotherapy is a good option.

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Angela is a 2018-2019 NEJM editorial fellow. She is an endocrine fellow who trained at Flinders Medical Centre and the Royal Adelaide Hospital. Angela recieved her medical degree from the University of Adelaide, and masters of public health from the University of Sydney. Her clinical and research interests are in the areas of glucocorticoid and cardiovascular endocrinology and diabetes medicine.