The prevalence of AKs varies depending on the region. In the United Kingdom, an estimated 6% of women and 15% of >40-years men have AKs. In Australia, the prevalence is higher, at 11%-40%, and in the Netherlands, 28% of women and 49% of men >45-years have AKs.1
The prevalence of AKs in South Africa is unknown, but it is likely to be high. South Africa is a sunny country with high levels of UV radiation. Additionally, South Africans have a high rate of skin cancer.5
Evolution of AKs
AKs follow one of three paths: 6,7,8,9,10,11,12,13
- Stable existence: A significant proportion of AKs remain stable (63.1%). They can, however, grow in size, and quantity, or become more hyperkeratotic if not treated.
- Spontaneous regression: In 20% to 23% of patients with a single lesion, and in up to 7.2% of patients with field cancerisation (presence of multiple AKs surrounded by an area of photodamaged skin) lesions may disappear spontaneously. However, lesions do recur in a significant number of patients (57%).
- Malignant transformation: Reported rates of progression of individual lesions to cutaneous squamous cell carcinoma (cSCC) range from 0.025% to 16%. Although most cSCCs can be successfully treated with surgery and radiation therapy, up to 7% of cases may metastasise, making treatment more challenging.
The five most important independent risk factors for AKs are:2,12,14
- Age: Up to 80% of individuals aged >60-years are affected
- Sex: More men are affected than women
- Phototypes I and II: Light-skinned individuals have less melanin pigment in the skin and tend to burn easily with sun exposure. Other characteristics of these skin phototypes may include red or blonde hair and blue or light-coloured eyes
- Family history of cutaneous neoplasms: Genetic factors may influence sensitivity to UV radiation
- Occupational sun exposure: Outdoor work is associated with a two-to three-fold increased risk of developing AKs. These workers are also at increased risk for cutaneous neoplasms, with an odds ratio (OR) of 3.67 for cSCCs, 3.32 for basal cell carcinoma (BCC), and 1.97 for melanoma.
Other risk factors that may play a role include episodes of painful sunburn <20-years (OR = 1.21), not using sunscreen (OR = 1.81), and exposure to tanning beds as mentioned above.2,14
Despite its limitations, the Olsen clinical grading system is often used in clinical practice:14
No pain, no gain
All lesions should be treated because predicting the progression of AKs is challenging. What is known is that patients with numerous lesions are at increased risk of progression to cSCCs.1,3,6,13
There are several treatment options available for AKs but the treatment mantra stays the same: No pain, no gain. Treatments are classified as lesion-directed (eg cryosurgery or ablative techniques), or field-directed (eg topical therapies, photodynamic therapy [PDT], dermabrasion, chemical peels).2,14
The advantage of field-directed treatments is that multiple, widespread, and subclinical AKs can be treated simultaneously. The primary goal of field-directed treatments is to reduce the risk of progression to cSCCs.2,14
Topical AK treatments include for example imiquimod, fluorouracil, and diclofenac, which are widely used to treat lesions. These agents have different mechanisms of action, dosages, and treatment durations. Treatment choice should be individualised based on the characteristics of the patient and his/her lesions.14
Imiquimod is safe and efficacious in the treatment of single, few, or multiple lesions. In South Africa, imiquimod 5% is approved for the topical treatment of superficial BCC, and clinically typical, non-hyperkeratotic, non-hypertrophic AKs on the face or scalp in adult patients.14,15,16
The 5% formulation can be used to treat small clusters of lesions in an area ≤25cm2 on the face and scalp. The recommended treatment schedule is three times a week (eg Monday, Wednesday, and Friday) over four weeks. The cream should be applied before normal sleeping hours and left on the skin for about eight hours.14,16
However, Del Rosso et al showed that imiquimod is also safe and effective to treat larger lesion sizes. The team investigated the safety and efficacy of multiple 16-week courses of imiquimod applied to large areas (>25cm2) of skin in adults with ≥4 AKs on the head, torso, and/or extremities. The team reported that the overall reduction in target lesion count was 80.2%, with an overall complete clearance rate of 36.4% and a partial clearance rate (≥75% reduction) of 68.6%.17
Sufficient cream should be applied to cover the treatment area. It is important the bear in mind that only a thin layer needs to be applied, because, unlike other topical treatments, imiquimod is a potent immuno-modulator, therefore less product is required. After a four-week treatment-free period, clearance of AKs should be assessed. If any lesions persist, treatment should be repeated for another four weeks.16
Patients should be informed that the cream may cause some expected side effects including erythema, flaking/scaling/dryness, and scabbing/crusting at the application site with normal dosing, due to its unique mode of action whereby it stimulates an immune response. The immune response is what causes these effects to occur. These local skin reactions may be severe, but generally decrease in intensity or resolve after cessation of treatment.15
Safety and efficacy
The safety and efficacy of imiquimod have been shown in numerous studies. One study showed that imiquimod 5% resulted in clearance of 75% of lesions, compared with 12% in the vehicle group. Another study showed that patients experienced an 86.6% reduction in the number of baseline lesions with imiquimod 5% compared to 14.3% for vehicle-treated patients following an eight-week treatment course.17
Long-term follow-up studies (one- to two-years post-treatment) showed continued clinical benefit of imiquimod treatment for AKs, with the majority of treated patients remaining clear, and low rates of recurrence. A meta-analysis comparing the efficacy of imiquimod 5% cream versus fluorouracil (5-FU) for the treatment of AKs on the face and scalp, concluded that imiquimod was more efficacious than 5-FU (70% vs 52%, respectively).17
Managing patients with single or few vs multiple lesions
The recommended lesion-directed treatment for single or few AK lesions is cryotherapy, while PDT (either with red light or daylight), is recommended for the treatment of multiple lesions on the face and scalp.18,19
When combined with cryotherapy, imiquimod can increase lesions' clearance and reduce recurrence rates. A study showed when imiquimod 5% cream was used post-cryotherapy, a significantly greater total number of AKs were cleared compared with vehicle (23% vs 9%).18,19
The first step in the management of patients with multiple AKs and field cancerisation is rigorous sun protection. Second-line therapy includes topical treatment. For patients presenting with multiple AKs, treatment is often targeted to the area of cancerisation, and the decision for specific treatment is determined by the size of this field and patient characteristics.20,21
A randomised, vehicle-controlled, split-face study explored the safety and efficacy of PDT followed by imiquimod. At month 12, median lesion reductions were 89.9% (PDT) versus 74.5% (sequential treatment), respectively. The author concluded that PDT followed by imiquimod was well tolerated and improved the reduction of AKs.22
Another study investigated whether the sequential use of PDT and imiquimod was more efficacious than each separately. They found that sequential application of PDT and imiquimod provides a significantly better clinical and histologic response in the treatment of AKs than monotherapy.23
Yet another study investigated the efficacy, tolerability, safety, and cosmetic outcome of sequential treatment with PDT and imiquimod. The team demonstrated that the sequential application of PDT and imiquimod is a well-tolerated method with high efficacy and safety and with an excellent cosmetic outcome.24
Patient experiences with imiquimod
According to Caperton and Berman, the ease, convenience, privacy, and autonomy associated with self-administration, treatment with imiquimod is preferred by patients over physician-administered modalities.19
Studies show that treatment with imiquimod has no clinically relevant impact on the health-related quality of life of patients and most patients exhibited good or acceptable tolerance to both PDT and imiquimod treatment.25,26
Imiquimod is now available in a unique storage and dispensing system (pump system) to further improve patient satisfaction. The advantages of the new pump system include:27
- Dispenses a controlled and precise amount of cream each time
- Easy to use for all patients, including elderly patients and those with limited agility
- Improves adherence to treatment
- Provides a consistent dose, which can improve efficacy
- Does not interfere with the imiquimod application technique
- Minimises product waste and loss
- Minimises excessive patient contact
- Minimises the occurrence of degradation during storage
- Simple and convenient to use
Overall, the pump system is a more accurate, effective, and user-friendly way to deliver imiquimod. It addresses many of the disadvantages of packages, such as imprecise dosing, manual delivery, and product waste. The pump system is also more compact and portable, making it easier to store and transport.27
- Calzavara-Pinton P, et al. Structured expert consensus on actinic keratosis: treatment algorithm focusing on daylight PDT. J Cutan Med Surg,2017.
- Marques E, Chen TM. Actinic Keratosis. [Updated 2022 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557401/
- Dirschka T, et al. Real-world approach to actinic keratosis management: practical treatment algorithm for office-based dermatology. J Dermatol Treat,2017.
- Lacour JP, et al. Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe. J Eur Acad Dermatol Venereol,2015.
- Cancer Association of South Africa. Fact Sheet on Actinic Keratosis. [Internet]. Available at: https://cansa.org.za/files/2021/01/Fact-Sheet-on-Actinic-Keratosis-January-2021.pdf
- Mpourazanis G, et al. The role and effectiveness of photodynamic therapy on patients with actinic keratosis: a systematic review and meta-analysis. Cureus,2022.
- Rosen T, Lebwohl MG. Prevalence and awareness of actinic keratosis: barriers and opportunities. J Am Acad Dermatol, 2013.
- Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. The Lancet, 1988.
- Lanoue J, Chen C, Goldenberg G. Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies. Cutis, 2016.
- Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol, 2000.
- Navarrete-Dechent C, Marghoob AA, Marchetti MA. Contemporary management of actinic keratosis. J Dermatol Treat, 2019.
- Reinehr CPH, Bakos RM. Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects. An Bras Dermatol, 2019.
- Heppt MV, et al. S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma—short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators. J Dtsch Dermatol Ges,2020.
- Del Regno L, et al. A Review of Existing Therapies for Actinic Keratosis: Current Status and Future Directions. Am J Clin Dermatol, 2022
- Professional Information. [Interrnet]. Available at: https://inovapharma.co.za/wp-content/uploads/2020/07/aldara-pi.pdf
- European Medicines Agency. [Internet]. Available at: https://www.ema.europa.eu/en/documents/product-information/aldara-epar-product-information_en.pdf
- Del Rosso JQ, et al. Safety and Efficacy of Multiple 16-week Courses of Topical Imiquimod for the Treatment of Large Areas of Skin Involved with Actinic Keratoses. J Clin Aesthet Dermatol, 2009.
- 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.
- Caperton C and Berman B. Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses. Clinical, Cosmetic and Investigational Dermatology, 2011.
- Piquero-Casals J, et al. Management Pearls on the Treatment of Actinic Keratoses and Field Cancerization. Dermatol Ther (Heidelb), 2020.
- Savary J, Tine MC, Weber AC, Dorey J. Management and clinical practice of multiple face and scalp actinic keratosis in France. J Mark Access Health Policy,
- Shaffelburg M. Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream. Journal of Drugs in Dermatology,
- Serra-Guillen C, et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. Journal of the American Academy of Dermatology,
- Held L, Eigentler TK, Leiter U, Garbe C, Berneburg MJ. Effective combination of photodynamic therapy and imiquimod 5% cream in the treatment of actinic keratoses: three cases. Biomed Res Int, 2013.
- Waalboer-Spuij R, et al. Patient Perception of Imiquimod Treatment for Actinic Keratosis and Superficial Basal Cell Carcinoma in 202 Patients. Dermatology, 2015.
- Serra-Guillen C, et al. A randomized comparative study of tolerance and satisfaction in the treatment of actinic keratosis of the face and scalp between 5% imiquimod cream and photodynamic therapy with methyl aminolevulinate. Br J Dermatol,
- National Center for Biotechnology Information. PubChem Patent Summary for US-9072876-B2. https://pubchem.ncbi.nlm.nih.gov/patent/US-9072876-B2. Accessed July 7, 2023.