View commentaries on this research

This is a plain English summary of an original research article

Comparison of four common treatment regimens for actinic keratosis found that twice daily 5% fluorouracil cream was the most effective and least expensive. It was also found to be convenient and well tolerated by patients.

Actinic keratosis, also known as solar keratosis, is a scaly skin lesion that develops following long-term sun exposure. It is a common disease in older adults that very occasionally can develop into skin cancer.

This Dutch study assessed 624 patients who had five or more actinic keratosis lesions on the head in one continuous area measuring 25 to 100 cm². Twelve months after the initial treatment, 75% of patients treated with fluorouracil cream achieved a reduction in number of skin lesions of at least 75%. This success rate was significantly better than for the other three treatments.

This trial provides a useful update to the literature on treatment for actinic keratosis and supports a simple regimen that can be started in primary care.

Why was this study needed?

About 20% to 33% of white people over 50 are affected by actinic keratosis, with incidence increasing with age. It is one of the most common reasons for visiting a dermatologist. If left untreated, it can occasionally develop into cancer. People also seek treatment for cosmetic reasons.

Patients often have recurring skin lesions, requiring repeated treatment. Although solitary lesions can be treated by freezing, patients often present with multiple lesions in one continuous area.

Many treatment options are available with a range of success rates and adherence. Treatments can be divided into ‘lesion-directed’ (treating individual lesions) or, ‘field-directed’ (treating multiple lesions within a larger area). Field-directed treatments are generally preferred because they may help to prevent the development of new lesions.

Previously, there had been limited trial evidence comparing different treatments and their long term outcomes.

What did this study do?

Four different commonly used ‘field-directed’ treatments for multiple lesions were compared in this randomised controlled trial. It involved 624 patients, with a median age of 73, attending four Dutch hospitals. Participants had five or more actinic keratosis lesions on the head, involving one continuous area of 25 to
100 cm². All grades of actinic keratosis lesions were included.

Patients were randomly assigned to four weeks of treatment with 5% fluorouracil cream or 5% imiquimod cream, or three days treatment with 0.015% ingenol mebutate gel, or a one-off treatment in the clinic of methyl aminolevulinate photodynamic therapy (MAL-PDT). (See the definitions tab for details). Patients achieving less than 75% reduction in keratoses following their initial treatment were offered a repeat treatment.

Although nearly half of eligible patients declined to participate in the trial, and 89% of participants were male, the design was robust, and the results are informative.

What did it find?

  • At 12 months after the end of treatment, the likelihood of achieving a 75% reduction in lesions was significantly higher among patients who received fluorouracil (75%, 95% confidence interval 67 to 81), than among those who received imiquimod (54%), MAL-PDT (38%), or ingenol mebutate (29%).
  • The percentage of patients with 100% treatment adherence was highest in the groups with shorter regimens: 99% in the ingenol mebutate group and 97% in the MAL-PDT group, compared to 89% in the fluorouracil group and 88% in the imiquimod group.
  • Patient satisfaction with treatment and increase in health-related quality of life were highest in the fluorouracil group. Results suggest this group may have experienced less inconvenience and discomfort with their treatment than those in other groups.
  • Cosmetic outcome was assessed by physicians as good-to-excellent more frequently in the MAL-PDT group (97%) and the ingenol mebutate group (95%) than in the fluorouracil group (90%) and the imiquimod group (90%).

What does current guidance say on this issue?

The British Association of Dermatologists’ NICE-accredited guidelines (2017) state that there is inadequate evidence to require treatment of all actinic keratosis lesions to prevent malignant cancers. Specialists recommend that an appropriate management plan should be devised between the patient and their doctor, taking into account the severity of symptoms, and other risk factors for cancer.

Patients can be treated by their GP, with referral to a specialist where they have not responded to treatment or where cancer is suspected. Patients should be educated about sun protection, as there is some evidence that use of sunscreen can reduce risks.

What are the implications?

Currently, variations in doctor and patient treatment choices are informed by many factors, including experience with side effects. The authors suggest that this trial could inform a more consistent treatment approach by dermatologists and GPs, with the potential to improve patient outcomes and reduce costs.

Limited UK data on current practice makes it hard to quantify these benefits, but healthcare commissioners may want to run analyses in their areas to guide prescribing practice.

Other treatment options targeted at individual actinic keratoses, such as freezing, are also available. These, a combination of treatments, or variations in concentration or duration of treatment may be useful for more severe or persistent cases.

Citation and Funding

Jansen M, Maud H and Janneke P. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380(10).

Funded by the Netherlands Organization for Health Research and Development. ClinicalTrials.gov number, NCT02281682.



De Berker D, McGregor J and Mohd M. British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol; 2017;176:20-43.

Gupta A, Paquet M and Villanueva E. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;(2):CD004415.

Uhlenhake, E E. Optimal treatment of actinic keratoses. Clin Interv Aging. 2013;8:29-35.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


  • Share via:
  • Print article


The four treatment regimens involved superficial curettage of the keratoses followed by one of:

  • 5% fluorouracil cream applied twice daily for four weeks
  • 5% imiquimod cream applied and washed off after eight hours, three times weekly for four weeks
  • methyl aminolevulinate photodynamic therapy (MAL-PDT): a cream is applied, then after three hours, the skin is exposed to phototherapy for a few minutes. The person must avoid sunlight for two days afterwards
  • 0.015% ingenol mebutate gel once daily for three days.

Patient achieving less than 75% reduction in keratoses following their initial treatment were offered a repeat treatment.



Expert commentary

The findings in this paper favour the use of one of the cheapest and most flexible treatments for actinic keratosis, which could open up the option of increased self-care for patients.

If GPs can take the central message that 5-fluorouracil cream is the agent of choice and can be used safely, then the likelihood of effective and economic treatment of actinic keratosis will increase.

It might also reduce referral of people with actinic keratosis to specialists and increase the possibility of flexible self-treatment by patients who become experts in managing this manifestation of sun damage, which is a chronic disease.

Dr David de Berker, Consultant Dermatologist, University Hospitals Bristol NHS Foundation Trust; University of Bristol Medical School; Lead author British Association of Dermatologists guideline on Actinic keratosis

The commentator declares no conflicting interests


Back to top