Clinical question

Which topical treatment should I choose for a patient with actinic keratoses?

In patients with multiple actinic keratoses on photodamaged skin, the aim is to treat the field of cancerisation, not only the visible lesions. In practice, the choice usually comes down to 5-fluorouracil (5-FU), imiquimod and tirbanibulin.

5-FU is the reference option when efficacy and clinical experience are the priorities. Imiquimod is an established alternative. Tirbanibulin is particularly useful when a very short, well-tolerated course is needed.

Before starting. Do not automatically treat a lesion that is indurated, painful, ulcerated, bleeding, markedly hyperkeratotic or clearly different. In these cases, Bowen disease or invasive squamous cell carcinoma should be excluded, and biopsy or referral considered.

1. 5-FU, imiquimod or tirbanibulin

5% 5-FU has the strongest comparative evidence at 12 months: in a direct trial it was more effective than imiquimod and also more cost-effective. This makes it a reasonable starting point in many patients, although the final choice depends on tolerability, regimen and patient preference.

Issue	5-FU	Imiquimod	Tirbanibulin 1%
When to choose it	When field control is the main priority.	When 5-FU is unsuitable or another first-line option is preferred.	When treatment duration and tolerability are the main priorities.
Regimen	4%: once daily for 4 weeks. 5%: according to product information and local protocol.	Intermittent regimens or cycles lasting several weeks, depending on formulation.	Once daily for 5 days.
Advantage	Strongest comparative support and extensive experience.	Effective and well-established alternative.	Very short course and usually shorter-lived local reactions.
Limitation	Visible inflammation, sometimes marked.	Longer regimen and less predictable inflammatory response.	Small treatment field, narrow indication and less comparative evidence.

In practice: choose 5-FU when efficacy is the priority; imiquimod when 5-FU is unsuitable; tirbanibulin when a five-day course may substantially improve adherence.

2. If I choose 5-FU: 4% or 5%?

The difference in concentration does not translate into a proportional difference in efficacy. In the direct comparison, complete clearance was 54.4% with once-daily 4% and 57.9% with twice-daily 5%. Clearance of at least 75% of lesions was virtually identical.

4% 5-FU

Once daily for 4 weeks. Very similar short-term efficacy, greater convenience and, overall, better tolerability.

5% 5-FU

The formulation with the strongest 12-month comparative evidence against other field treatments.

Practical choice

4% is very reasonable when adherence and tolerability are priorities. 5% is particularly relevant when aiming to reproduce the option with the best comparative evidence.

With either formulation, patients should expect erythema, scaling, crusting and possible erosion. Explain what is expected and when medical advice is needed.

3. Where should tirbanibulin be positioned?

Its main advantage is a five-day course. Under the European product information, it is indicated for Olsen grade I, non-hyperkeratotic and non-hypertrophic actinic keratoses on the face or scalp, within a field of up to 25 cm².

It is particularly suitable when

• the field is small and located on the face or scalp;
• lesions are thin and non-hyperkeratotic;
• the patient is unlikely to complete several weeks of treatment;
• prolonged visible inflammation would create work or social difficulties.

It would not be my first choice when

• the field is extensive;
• lesions are thick, infiltrated or clinically suspicious;
• the strongest evidence for sustained control is the main priority;
• automatic repeat courses are being considered or the patient is immunocompromised.

Review response at approximately 8 weeks. If complete clearance has not been achieved, reassess the diagnosis and management plan.

Pocket algorithm

1. Confirm that there are several thin actinic keratoses.
2. Remove any suspicious lesion from the algorithm.
3. Choose according to the main priority: efficacy, tolerability or treatment duration.
4. Explain the expected reaction and arrange follow-up.

Knowledge gaps

• Immunocompromised patients: too few trials define the best strategy.
• Prevention of squamous cell carcinoma: reducing actinic keratoses is not the same as proving a sustained reduction in invasive carcinoma.
• Tirbanibulin: direct comparisons with 5-FU and imiquimod are lacking, as are stronger data on retreatment and long-term control.

Take-home message

In an immunocompetent patient with several thin actinic keratoses, 5-FU is usually the most practical first choice. The 4% formulation improves convenience and tolerability; 5% has the strongest comparative evidence. Imiquimod remains a valid alternative. Tirbanibulin is especially useful when a five-day course may clearly improve adherence.

Main sources

1. Jansen MHE et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019;380:935-946. Open source.
2. Jansen MHE et al. Trial-based cost-effectiveness analysis of topical field treatments. Br J Dermatol. 2020;183:738-744. Open source.
3. AEMPS-CIMA. Tolak 40 mg/g crema: ficha técnica. Open source.
4. Blauvelt A et al. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. N Engl J Med. 2021;384:512-520. Open source.
5. European Medicines Agency. Klisyri: European product information. Open source.

Content intended for healthcare professionals. Always adapt treatment to current product information and the individual patient.