Studies show that the prevalence rates of AK are 18% in tropical, 2% in subtropical, and 18% in temperate regions. In individuals >60-years, the prevalence is ~15%, with men being more affected (24%) than women (14%).²

AK lesions are generally asymptomatic but can sometimes cause itching or stinging. The diagnosis of AK is primarily based on its clinical appearance, though non-invasive imaging techniques such as dermatoscopy, are useful diagnostic tools. Histomorphologically, AK have various variants, including atrophic, hypertrophic, acantholytic, pigmented, lichenoid, and Bowenoid types.³

When multiple or recurrent AK lesions appear on sun-exposed skin, this is referred to as field cancerisation. Field cancerisation is often triggered by ultraviolet radiation damage to the p53 gene and can lead to the clonal expansion of cancer-primed cells, forming a contiguous patch of altered cells.³

No pain, no gain

The primary goals of AK treatment are to eliminate as many clinical and subclinical lesions as possible, achieve long-lasting remission, ensure a good cosmetic outcome, and prevent progression to invasive SCC.³

The phrase 'no pain, no gain' is often linked to AK treatment, suggesting that effective therapies may come with some level of discomfort or side effects. Treatment plans should be tailored taking factors such as lesion characteristics, patient preferences, treatment availability, and cost into consideration. Urgent intervention is needed for rapidly growing, painful, or bleeding lesions to prevent complications.¹

Treatment options for AK are categorised into lesion-directed and field-directed therapies. Lesion-directed treatments focus on individual lesions and include cryotherapy, curettage, and surgical excision, which are effective for targeting visible AK.¹

Field-directed therapies treat larger areas of skin affected by sun damage and target both visible and subclinical lesions. Therapies include topical medications such as imiquimod and 5‑fluorouracil (5-FU), as well as photodynamic therapy (PDT).^1,3

The most widely used topical agents for the field-based treatment of multiple AK are imiquimod and 5-FU. In South Africa, imiquimod is indicated for the treatment of clinically typical, non-hyperkeratotic, non-hypertrophic AK on the face or scalp in adult patients. 5-FU is indicated for the treatment of AK.^4,5,6

Imiquimod is a topical immune-response modifier that acts as a toll-like receptor-7 agonist, stimulating the innate and adaptive immune systems. It activates dendritic cells, monocytes, macrophages, and Langerhans cells, promoting the release of cytokines and chemokines, while also inducing apoptosis in tumour cells.³

Imiquimod cream is typically applied three times a week (eg Monday, Wednesday, and Friday) before bedtime and left on the skin for about eight hours. The initial treatment period lasts four weeks, after which a four-week break is recommended. During this break, a healthcare professional will assess the treated area to determine if the AK has cleared. If AK persists, treatment can be extended for an additional four weeks, with a total maximum treatment duration of eight weeks. Clearance of AK should be evaluated four to eight weeks after each treatment cycle.⁵

5-FU, a pyrimidine analogue and antimetabolite, works by inhibiting thymidylate synthase, an enzyme essential for DNA synthesis and RNA function. 5-FU can be applied once or twice daily for two- to four-weeks, up to a maximum of 12-weeks. 5-FU is effective for treating both single lesions and large areas of AK.³

PDT is a minimally invasive treatment that targets malignant cells using photosensitisers like 5-aminolevulinic acid (5-AMA and 5-methyl aminolevulinate (5-MAL). These agents accumulate in abnormal cells and, when exposed to light, produce reactive oxygen species that cause cellular damage and necrosis.³

Efficacy of imiquimod

Several studies have demonstrated the efficacy of imiquimod cream in treating AK. Imiquimod showed significant lesion reduction compared to a vehicle.⁷

A cycling treatment approach led to complete clearance in 82% of cases, while phase III trials reported clearance rates of 45.1% and 57.1% for imiquimod, with low discontinuation rates.⁷

Imiquimod, when combined with cryotherapy, further increased lesion clearance rates. In immunosuppressed patients, the cream was well tolerated without impacting graft function.⁷

The most common adverse effect of imiquimod cream is a localised skin reaction at the application site, including erythaema, itching, burning, and pain.⁷

In terms of long-term treatment, Del Rosso et al assessed multiple 16-week courses of imiquimod for treating extensive AK (mean treatment area of 625cm²). Participants applied imiquimod twice weekly for 16 weeks, with additional courses available if needed. Most participants tolerated the treatment well, though 40.5% reported adverse events, and 31.4% experienced severe erythaema.⁸

Overall, imiquimod reduced AK lesions by 80.2%, with a complete clearance rate of 36.4% and a partial clearance rate of 68.6%. Despite some skin reactions, multiple treatment courses effectively reduced AK in patients with large, affected areas.⁸

Recurrent AK

AK is a chronic, unpredictable skin condition, characterised by the development of new lesions and recurring episodes. Some lesions may regress spontaneously (rates range from 15% to 63% per year), however, despite initial clearance, long-term recurrence rates are high, ranging from 39% to 85%. Possible causes why AK may recur include non-adherence to treatment, misdiagnosis, or, though rare, malignant transformation to SCC.^1,9,10,11

Because of its chronic nature, AK requires long-term treatment and management of lesions and the surrounding fields to prevent recurrence and potential progression to malignancy.¹

Imiquimod cream has shown strong efficacy in the long-term treatment of AK, achieving high clearance rates in multiple studies. In a pilot study, 75% of AK lesions cleared with imiquimod compared to 12% in the control group.⁷

Other studies have demonstrated complete clearance rates of 45% to 57%, with lesion reductions of up to 86% following 16-week treatment courses. Long-term follow-up indicates sustained benefits, with many patients remaining clear one to two years after treatment and recurrence rates staying low.⁷

In combination with other treatments, such as cryotherapy, imiquimod further enhances clearance rates. When used post-cryotherapy, lesion clearance increased significantly (87% vs 50% with cryotherapy alone). Additionally, lower concentrations (2.5% and 3.75%) of imiquimod also showed effective lesion clearance, with sustained results observed at one year. Overall, imiquimod has shown to be an effective long-term solution for AK management.⁷

Krawtchenko et al compared the clearance efficacy of cryosurgery, imiquimod, and 5-FU in treating AK. Initial clinical clearance was highest in the 5-FU group (96%), followed by imiquimod (85%) and cryosurgery (68%). Histological clearance rates were higher at 73% for imiquimod, followed by 67% for 5-FU, and 32% for cryosurgery.¹²

After 12-months, imiquimod showed the highest sustained clearance rate for individual lesions (73%) and total treatment field (73%), compared to 5-FU (54%) and cryosurgery (28%).¹²

Additionally, patients in the imiquimod group had the best cosmetic outcomes. Given its superior long-term efficacy and cosmetic benefits, imiquimod should be considered a first-line treatment for AK, concluded Krawtchenko et al.¹²

In their real-world study, Neugebauer et al compared the long-term efficacy of imiquimod and 5-FU in reducing the risk of recurrent AK. They found that although 5-FU was effective in the short-term, it is not more effective in the long-term (five-years) as with imiquimod.⁴

Patient satisfaction = adherence to treatment

According to Caperton and Berman, patient preference should guide treatment, because clearance rates are significantly enhanced with good adherence to a treatment regimen.⁷

In their study, Caperton and Berman found that patients prefer imiquimod due to the ease, convenience, privacy, and autonomy associated with self-administration.⁷

Furthermore, a prospective, non-randomised pilot study found that imiquimod achieved a median Treatment Satisfaction Questionnaire for Medication score of 72.7 for effectiveness, and a global satisfaction score of 69.4.¹³

Imiquimod scored a high satisfaction score regarding side effects, with a median of 93.8. Furthermore, 72% of imiquimod-treated patients expressed a preference for repeating the same treatment.¹³

Conclusion

AK are chronic and unpredictable, with long-term recurrence rates ranging from 39% to 85%. Despite initial clearance, AK lesions often reappear due to factors such as non-adherence to treatment or misdiagnosis. Imiquimod cream has demonstrated strong efficacy in reducing AK recurrence, with complete clearance rates between 45% and 57% and lesion reductions of up to 86%. Long-term studies show sustained benefits, with many patients remaining lesion-free for one to two years post-treatment. When combined with cryotherapy, imiquimod further enhances clearance rates and offers a reliable, long-term solution for managing recurrent AK.

References

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2. George CD, Lee T, Hollestein LM, et al. Global epidemiology of actinic keratosis in the general population: a systematic review and meta-analysis. BMJ Dermatology, 2024.
3. Del Regno L, Catapano S, Di Stefani A, et al. A Review of Existing Therapies for Actinic Keratosis: Current Status and Future Directions. Am J Clin Dermatol, 2022.
4. Neugebauer R, Levandoski KA, Zhu Z, et al. A real-world, community-based cohort study comparing the effectiveness of topical fluoruracil vs. topical imiquimod for the treatment of actinic keratosis. Am Acad Dermatol, 2018.
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9. Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol, 2021.
10. de Berker D, McGregor JM, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol, 2017.
11. Steeb T, Wessely A, Petzold A, et al. Long-term recurrence rates of actinic keratosis: A systematic review and pooled analysis of randomized controlled trials. J Am Acad Dermatol, 2022.
12. Morton C, Baharlou S, Basset-Seguin N, et al. Expert recommendation on facilitating personalized approaches to long-term management of actinic keratosis: The Personalizing Actinic Keratosis Treatment (PAKT) Project. Acta Derm Venereol, 2023.
13. Krawtchenko N, et al. A randomised study of topical 5 % imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol, 2007. 
14. Khanna R, Bakshi A, Amir Y, Goldenberg G. Patient satisfaction and reported outcomes on the management of actinic keratosis. Clinical, Cosmetic and Investigational Dermatology, 2017.