Debate about the optimal management of actinic keratoses (AKs) shows no signs of abating. Opinion differs on whether they all should be treated and, if they are treated, whether intervention should be confined to the lesions themselves, directed at the area affected by field change or both. Evidence of efficacy and tolerability of recently introduced drugs has prompted clinicians to re-evaluate management and reconsider their approach to treatment. Patient preference has always been an important determinant of treatment; now there is more choice and new treatment regimens to support greater concordance.
A group of leading dermatologists discussed how these issues will affect clinical practice at a meeting held at the Royal College of Physicians in London on 21 March 2013. The Chair, Dr Stephen Kownacki, Executive President of the Primary Care Dermatology Society (www.pcds.org.uk), Dr Colin Morton (Consultant Dermatologist, Falkirk and District Royal Infirmary), Dr Girish Gupta (Consultant Dermatologist and West of Scotland Skin Cancer Lead Clinician, NHS Lanarkshire), Dr Jonathan Bowling (Consultant Dermatologist and Honorary Senior Clinical Lecturer, Oxford University Hospitals NHS Trust) and Dr Christopher Bower (Consultant Dermatologist, Royal Devon and Exeter NHS Foundation Trust) reviewed the optimal management of AKs and the likely impact of new treatments.
What is current practice?
There are currently three guidelines for the management of AKs. The UK guideline was published in 2007,1 predating some of the treatments now available; it is now being updated. It acknowledges the differing views about whether or not to treat AKs, but makes no specific recommendation about treatment choice or the role of field-directed or lesion-specific treatment.
The European guideline, developed by the European Dermatology Forum, identifies many risk factors for progression of AKs to squamous cell carcinoma (SCC) – duration, course, localisation and extent of lesions, solitary or multiple AKs, age, comorbidity, adherence, pre-existing skin cancer and immunosuppression. However, it does not adopt a risk-based approach, instead recommending that all AKs are treated because of the risk that they may progress.2
The UK Primary Care Dermatology Society (PCDS) guidance, the most recently updated advice, makes the clearest distinction between a field-directed and lesion-specific approach3 and most closely reflects current UK practice. It states that treatment should be directed at the lesion and not the surrounding skin when there are few lesions or larger numbers that are widely distributed. Patients with field change should have more vigorous treatment applied to the affected area and not just the individual lesions.
None of these guidelines is directive about treatment choice, opting instead to outline the options available. As a result, clinical practice varies according to local specialist opinion, commissioning arrangements and the constraints of drug formularies. This leaves several unresolved questions:
• Should AKs be treated?
• If treatment is indicated, should it be field-directed or lesion-specific?
• What are the challenges in prescribing a topical treatment for AK?
Actinic keratoses: to treat or not to treat?
In the UK, the decision to treat depends on risk stratification, prioritising treatment for individuals at high risk due to the presence of risk factors. This conflicts with the European guidelines, which recommend treating all AKs, but it should be recognised that in the UK most treatment is provided by GPs whereas in many European countries it is provided by specialists.
There is currently no evidence that treating AKs prevents SCCs. Such a finding, which is both logical and expected, would greatly strengthen the case for treating AKs. However, evidence from Australia has shown that prescribing effective sun protection does reduce the incidence of AK and SCC.4 Uncertainty about the risk of progression is likely to be an impediment to treatment in primary care.
Dermatologists agree that treatment must be tailored to the needs of each patient and that patient preference strongly influences the decision whether to treat and the choice of treatment. Some patients tolerate the appearance of AKs and the possible risk of progression, whereas others request treatment; similarly, there are different attitudes to adverse effects and prolonged treatment regimens. It should be emphasised that treating AKs is not a question of cosmetic acceptability but one of preventing progression to SCC. More aggressive treatment is warranted in patients at increased risk of progression.
Diagnosis and referral
Dermatologists and GPs are seeing more patients with AK or SCC than in the past and their management now forms a major part of a dermatologist’s workload. This is predominantly due to the increase in the population of older people and the chronic effects of sun damage on exposed skin. This has increased demand for treatment, fuelled by growing patient awareness that effective treatments are available.
Dermatologists usually follow the wishes of their patients regarding whether or not to treat. The secondary care perspective can be summarised as suspicion that a lesion is potentially malignant until proven otherwise. This is feasible because dermatologists see only the tip of the AK iceberg and the patients they do see tend to have more serious lesions. Some clinicians feel that it is difficult to deny a patient treatment for what is a potentially premalignant lesion. In primary care, GPs see many more patients with less serious skin lesions and generally take the view that the lesion is benign unless there are grounds to suspect otherwise. However, diagnosis of AKs and SCCs can be difficult and some GPs lack confidence in their diagnostic skills. This underlines the importance of education to enable GPs to first diagnose and then to distinguish between high- and low-risk lesions more reliably.
Dermatologists cannot supervise the treatment of all the patients referred to them and they are encouraged by their Trust or Health Board to discharge patients after diagnosis or, when indicated, initial therapy. It is therefore essential that patients discharged into primary care have a management plan that has been agreed with the GP.
The advent of clinical commissioning groups (CCGs) and renegotiation of contracts with providers has brought further uncertainty to funding for referral and treatment of AK. The management of AKs should be included in the bundle of care commissioned for older people, but there is a trend for commissioners, faced with the need to prioritise funding, to refuse to pay for the treatment of apparently benign lesions. While this is currently applicable to lesions such as seborrhoeic keratoses and warts, it is uncertain whether the management of AKs could be affected in the future. It is possible that funding may inappropriately be directed towards more costly and less effective procedures that generate income (eg cryotherapy) rather than topical treatment. CCGs will monitor referrals and intervene if a GP’s referral rates exceed the norm. These issues reinforce the importance of risk stratification as a means of prioritising patient care.
NICE recommends that the initial management of AKs is provided in primary care.5 One approach to improving the efficiency of diagnosis and referral would be to train selected GPs in a locality so that they could provide a pre-referral triage service to increase the proportion of patients seen by dermatologists who are at high risk. This strategy has proved effective in Australia, where dermatologists now see few cases of melanoma because they are being diagnosed by trained GPs.
Wider use of dermoscopy may also help to improve diagnosis. Although telemedicine may be a useful option in some circumstances, the value of a face-to-face consultation is that a physical examination can sometimes identify high-risk lesions other than the one prompting the referral.
Field-directed or lesion-specific treatment?
What is the rationale for field-directed treatment?
Current data suggest there is a continuum of disease linking the formation of AKs with the development of SCCs.2 The creation of early AKs is due to damage from UV radiation. These damaged cells are subclinical, but may develop into visible AKs if they are not cleared by immune surveillance. If sufficient gene damage persists with further exposure to UV radiation, the AK may develop into an SCC, which, if unchecked or not diagnosed, may metastasise. It is not possible to predict which AKs will progress to SCCs. Although estimates of the risk of progression for a single lesion vary from 0.025% to 16%,6 it is likely that the true figure is <1%. Many people with AK have multiple lesions,7–9 and the risk of progression may be as high as 14% in individuals with at least 10 lesions.3 The risk of progression is also increased for AKs that are thickened and when they occur in individuals who are immunosuppressed.
AKs are rarely isolated lesions.2,10 A UV-exposed area is associated with extensive field damage (also known as field ‘cancerisation’, although this is likely to be a worrying term for patients). An area of field damage contains foci of mutated keratinocytes, subclinical AKs, clinical AKs and SCC. Field change is likely when visible lesions occur in close proximity, but it is believed that invisible subclinical lesions occur up to 10 times more often than visible AKs.
Treating field change is as important as treating a visible lesion and most dermatologists will do both. When patients have field change with photodamaged skin and visible lesions, it is rational to treat the field first then the remaining lesions. When treating field change, it is rational to treat a cosmetic unit (ie large regions of the face or the entire scalp), rather than risking cosmetically unacceptable results by treating several adjacent smaller areas in sequence. Patient preference should be taken into consideration, so it is important that patients are educated about the clinical significance of field change.
The true extent of field damage and treatment efficacy: Lmax
Endpoints traditionally used in clinical studies of the treatment of AKs – complete and partial clearance rates, percentage change in lesion numbers – were developed to assess lesion-directed therapies. They measure the change in visible lesions from baseline to the end of the treatment period, usually in a limited area of skin. While they are suitable for treatments that target visible lesions, such measures do not assess subclinical lesions in skin with field damage. They do not reflect the full extent of AKs and therefore underestimate the efficacy of field-directed treatments.
During treatment with imiquimod 3.75% cream (Zyclara), there is an increase in the number of visible lesions because stimulation of the local immune response causes disclosure of subclinical lesions, revealing the full extent of clinical and subclinical disease. This occurs with imiquimod 3.75% cream during both treatment periods, although the effect is usually more marked during the first.
Lmax, defined as the maximum number of lesions visible during treatment, has been proposed as a new measure to assess the true extent of field damage according to the number of visible AKs and subclinical lesions that become apparent during treatment with imiquimod. The effectiveness of treatment is assessed by comparing Lmax with the lesion count at a defined interval (usually eight weeks) after the end of treatment.
Figure 1 illustrates this concept graphically and includes a case study to illustrate its clinical significance. In this example, there were 10 lesions at baseline. Lmax was 24 and at the final assessment there were two lesions. The reduction in lesion count from Lmax was therefore 22, whereas the reduction for baseline lesion count was only eight. The photographs illustrate how changes in the number of visible lesions during treatment with imiquimod 3.75% correspond to Lmax.
Lmax requires validation by confocal microscopy before it can be more widely utilised. However, it appears to offer a simple and clinically feasible means of measuring the true extent of clinical and subclinical AKs and the effectiveness of treatment.
What are the challenges in prescribing a topical treatment for AK?
Dosing and administration
Options for field-directed treatment of AKs are summarised in Table 1. Treatments that are not lesion-specific, ie imiquimod 5% cream and ingenol mebutate gel, are licensed for application to areas no greater than 5 x 5cm2. By contrast, imiquimod 3.75% cream can be applied to a large field, up to 200cm2 (the entire scalp or face).
Dermatologists may not adhere closely to restrictions on the area of application, but they are reluctant to use most older products to treat large areas of field damage due to their adverse effects. This has several implications: treatment of large fields takes longer with older products because they must be applied to small areas in turn; this sequential approach creates a grid appearance on the skin that may be more cosmetically obvious than the original lesions; and workload is increased due to the need for repeat visits to treat each area.
Current efficacy endpoints (eg complete and partial lesion clearance rates from baseline) do not capture the clearance of subclinical lesions that may become visible during treatment, and so may underestimate the true efficacy of field-directed AK therapies. Lmax, the new efficacy parameter, is a measure of the maximum number of lesions that are visible during the treatment phase. This includes visible lesions at baseline and subclinical lesions that appear during the course of treatment (Figure 2).
Imiquimod 3.75% cream makes subclinical lesions visible and effectively treats up to 92% of all AK lesions.13 A long-term benefit of sustained clearance was achieved with imiquimod 3.75% cream in 40.5% of patients after 12 months.14
Most other treatments are not truly field-directed due to the limitation on the size of area that can be treated. Diclofenac 3% in sodium hyaluronate is better tolerated than other treatments. However, the rate of adherence to the prolonged treatment regimen achieved in clinical trials is difficult to emulate in primary care and the trials are therefore possibly unrepresentative of everyday practice.
Imiquimod 3.75% cream is already being used in England, Scotland and Wales. It has been approved by the All-Wales Medicines Strategy Group. Where imiquimod 5% cream is already on a formulary, there may be no need for further approval to use the lower strength formulation. In some areas that adopt a one in, one out policy, imiquimod 3.75% cream may replace imiquimod 5%. It is now being considered by the Scottish Medicines Consortium but is not yet being appraised by NICE.
In clinical trials, application site reactions with imiquimod 3.75% cream were predominantly mild to moderate in severity;14 less severe than with the higher strength imiquimod. Clinicians and patients who have previously had a marked reaction with imiquimod 5% cream may be wary of using imiquimod again, but clinical experience shows that patients previously treated with imiquimod 5% experience a less severe reaction with imiquimod 3.75% and can be reassured.
Clinical experience shows that application-site reactions with imiquimod 3.75% cream tend to occur after the completion of the two-week application period; treatment is therefore not usually interrupted. If a reaction does occur during the application period, treatmentcan be suspended for a few days and recommenced when symptoms have improved. This interruption does not impair efficacy and there is no need to extend the treatment period.
Adherence to treatment
Application-site reactions cause distress and inconvenience to patients and, if they prompt patients to return for another consultation, they increase GPs’ workloads. Measures to support patients are therefore welcome and may include a telephone helpline or contact with a specialist nurse. Such support may also reduce the number of patients who stop their treatment, or decline a second course, as a result of adverse effects.
Patients are more likely to continue treatment with imiquimod 3.75% cream if they are informed about the likelihood that visible lesions will transiently increase and other possible adverse effects, so that they know what to expect. This is covered by written information now available for the physician to give to the patient, but it has not been possible to include this in the product packaging. It is therefore important for clinicians to counsel the patient. Information will be available online in the future.
Low adherence due to the prolonged treatment period necessary for some products is probably a major cause of treatment failure, but the dose schedule of imiquimod 3.75% cream is likely to be more appealing to patients and GPs than that of other treatment options. It can be difficult, even for specialists, to remember the dose regimens of all the products indicated for AK treatment. The simplicity of the dose regimen for imiquimod 3.75% cream is a useful advantage for prescribers and patients. The recommended dose is once daily before bedtime to the affected field for two treatment cycles of two weeks each, separated by a two-week no-treatment period. The total duration of six weeks is less than half that required for diclofenac 3% in sodium hyaluronate (typically 90 days) and once-daily application is easier to remember than the thrice-weekly schedule of imiquimod 5% cream.
Dermatologists wishing to initiate treatment with imiquimod 3.75% cream may prescribe treatment themselves and then ask the GP to take over responsibility, or they can recommend that the GP prescribes it from the outset. GPs who lack confidence in their diagnostic skills may be reluctant to treat AKs without the support of a dermatologist, and the need to manage application-site reactions may be a further deterrent. It is therefore important that GPs have access to education about the management of AKs.
Patients should be educated about skin protection and made more aware of AKs and their treatment. Initiatives should be focused on older people with appropriate print and online media. While there are obvious advantages in having an educated patient population, there is a risk that this approach might increase public anxiety and the number of patients consulting for suspected AKs. Options to manage this demand include training community pharmacists to recognise high-risk lesions, although this would require funding. Pharmacies could also be used to provide written information about AKs. Educational initiatives could be usefully combined with practical steps to promote skin protection, such as providing free sun hats.
AKs are taking up a growing proportion of dermatologists’ workloads and it is likely that in the future much of this workload will shift into general practice. The increasing range of drugs available to treat AKs is welcome as it provides both clinicians and patients with a wider choice. Although there is a lack of evidence on which to base the selection of treatment, clinical factors and patient preference should guide choice. The new lower strength 3.75% imiquimod cream is a particularly welcome addition to the armamentarium of field-directed treatments, with its good efficacy, once-daily administration and short-duration dosing regimen.
1. de Berker D, McGregor JM, Hughes BR, et al. Guidelines for the management of actinic keratoses. Br J Dermatol 2007;156:222–30.
2. Stockfleth E, Terhorst D, Braathen L, et al. Guidelines for the management of actinic keratoses. European Dermatology Forum. Update 2011 (www.euroderm.org/images/stories/guidelines/guideline_Management_Actinic_Keratoses-update2011.pdf; accessed 2 May 2013).
3. Primary Care Dermatology Society. Actinic keratosis. January 2013 (www.pcds. org.uk/clinical-guidance/actinic-keratosis-syn.-solarkeratosis#management;accessed 2 May 2013).
4. Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723–9.
5. National Institute for Health and Clinical Excellence. Guidance on cancer services. Improving outcomes for people with skin tumours including melanoma: the manual. February 2006 (www.nice.org.uk/nicemedia/live/10901/28906/28906.pdf; accessed 2 May 2013).
6. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42:23–4.
7. Harvey I, Frankel S, Marks R, et al. Non-melanoma skin cancer and solar keratoses. I. Methods and descriptive results of the South Wales Skin Cancer Study. Br J Cancer 1996;74:1302–7.
8. Alexiades-Armenakas MR, Geronemus RG. Lasermediated photodynamic therapy of actinic keratoses. Arch Dermatol 2003;139:1313–20.
9. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinatephotodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008;158:994–9.
10. Jeffes EW, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol 2000;1:167–79.
11. Joint Formulary Committee. Photodamage. British National Formulary No. 65. May 2013.
12. Berman B, Cohen DE, Amini S. What is the role of field-directed therapy in the treatment of actinic keratosis? Part 1: overview and investigational topical agents. Cutis 2012;89:241–50.
13. Stockfleth E, Alomar A. Lmax as a novel efficacy parameter for field-directed treatment of actinic keratosis: results with imiquimod 3.75% versus placebo. Poster presentation, EADV 2012.
14. Hanke CW, Swanson N, Bruce S, et al. Complete clearance is sustained for at least 12 months after treatment of actinic keratoses of the face or balding scalp via daily dosing with imiquimod 3.75% or 2.5% cream. J Drugs Dermatol 2011;10:165–70.