What are the recommended topical treatment options for actinic (solar) keratosis in adults, including first‑line agents and alternatives?

Topical Treatment Options for Actinic Keratosis

For isolated actinic keratoses (1-3 lesions), cryosurgery with liquid nitrogen is the first-line treatment, while for multiple lesions in a contiguous area, field-directed therapy with 5-fluorouracil or imiquimod is strongly recommended. 1, 2

Treatment Selection Algorithm

For Isolated or Few Lesions (1-3 AKs)

Cryosurgery with liquid nitrogen is the preferred first-line approach, offering:

• Clearance rates of 57-98.8% depending on technique and follow-up duration 2, 3
• Single office visit convenience 2
• Superior outcomes with longer freeze times: >20 seconds achieves 83% clearance versus <5 seconds achieving only 39% clearance 2, 3

For Multiple Lesions in a Contiguous Field

Field-directed topical therapy is strongly recommended when multiple AKs are present 1, 2. The hierarchy of topical agents based on efficacy:

First-Line: 5-Fluorouracil (5-FU)

• Highest efficacy among all topical field treatments 2, 4
• Complete clearance in 55% of patients at 8 weeks post-treatment 2
• FDA-approved for multiple actinic keratoses 5
• The 0.5% formulation in 10% salicylic acid is particularly useful for scalp lesions 3
• Approximately 50% of patients discontinue at 6 weeks due to lesion disappearance 2

First-Line: Imiquimod

• Strongly recommended with high-quality evidence 1, 2
• Complete clearance rates of 44-46%, with 76% maintaining clearance at 12 months 2, 4
• FDA-approved for clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on face or scalp in immunocompetent adults 6
• Better tolerated than 5-FU with fewer local reactions 7

First-Line: Tirbanibulin

• Strongly recommended with high certainty evidence by the American Academy of Dermatology 1
• Significantly shorter treatment duration: 5 consecutive days only 1, 3, 4
• Complete clearance in 49.3% of patients by day 57 1, 2
• FDA-approved for topical field treatment of actinic keratosis on face or scalp 8
• Most common adverse events: application site pruritus (9.1%) and pain (9.9%), with <1% experiencing severe local reactions 1
• No treatment discontinuations due to adverse events in clinical trials 1

Site-Specific Considerations

Face and Scalp

• All three first-line topical agents (5-FU, imiquimod, tirbanibulin) are strongly recommended 1, 2, 4
• Confluent scalp lesions respond well to any of these options 3
• Pretreatment with 5% salicylic acid ointment may improve outcomes by reducing hyperkeratosis 3

Ears

• Require early aggressive treatment due to higher risk of metastasis if progression to SCC occurs 4
• Grade 3 (thick) AKs on the ear warrant curettage early to obtain histology and exclude early invasive SCC 1, 4
• Cryosurgery, 5-FU, and imiquimod all receive excellent ratings for facial/ear lesions 4

Dorsum of Hands

• Skin is more resistant to treatment than head and neck, requiring extended treatment periods 1
• Multiple and hyperkeratotic lesions are common 1
• Combinations of salicylic acid with 5-FU or curettage can be useful for thick (grade 3) AKs 1

Below the Knee

• Requires flexible, low-intensity regimens due to poor healing capacity in elderly patients 1
• Infrequent or pulsed application of 5-FU (once weekly under occlusive bandage for 7 days over 4-8 weeks) has been employed 1
• Diclofenac 3% gel may be considered for fewer side effects, though with possibly less benefit 1
• Photodynamic therapy is preferred where healing problems are anticipated 1

Combination Therapy Approaches

Combining topical field agents with cryosurgery may improve outcomes:

• 5-FU + cryosurgery is conditionally recommended over cryosurgery alone (moderate quality evidence) 2, 4
• Imiquimod + cryosurgery is conditionally recommended over cryosurgery alone (low quality evidence) 2, 4

Critical Management Pitfalls to Avoid

Thick or Treatment-Resistant Lesions

Obtain histology immediately for any AK that is:

• Thick or hyperkeratotic 1, 3
• Fails to respond to standard therapy 2
• Exhibits concerning features (see below) 2

Warning Signs Requiring Urgent Reassessment

The following features may signal progression to invasive SCC and require immediate biopsy or referral 2:

• Spontaneous or easily induced bleeding
• New pain or tenderness
• Rapid increase in size
• Development of palpable thickness or induration
• Lack of response to standard therapy

UV Protection is Non-Negotiable

• UV protection is as important as lesion-directed therapy for preventing new AKs 2
• Daily broad-spectrum sunscreen and protective clothing are mandatory 2
• Wide-brimmed hats are essential for scalp protection 3

Special Populations

Immunosuppressed Patients

• Higher risk of progression to SCC (21% in field-change AK versus 7% in isolated AK within one year in transplant recipients) 1
• Treatments are less effective than in immunocompetent patients 1
• Require shorter follow-up intervals and more aggressive monitoring 1
• Imiquimod safety and efficacy have not been established in immunosuppressed patients 6

Periocular Region

• All licensed treatments include warnings about use near the eye 1
• Requires careful assessment in secondary care with clear guidance and supervision 1

Follow-Up and Monitoring

Actinic keratosis is a chronic, managed condition requiring ongoing surveillance:

• Recurrence rates reach up to 50% within the first year after successful treatment 2, 4
• Patients with ≥10 AK lesions have a 3-fold increased risk of developing SCC and require shorter follow-up intervals 2, 3
• Regular dermatology follow-up for early detection of new lesions is essential 2
• Patient education for ongoing self-examination is critical 2