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Developments in treating actinic keratosis

 

 

Picato® contains the active ingredient ingenol mebutate purified from the Euphorbia peplus plant, and is a new, fast-acting, treatment option for actinic (solar) keratosis
Rod Tucker PhD MRPharmS
Honorary Research Associate,
Faculty of Health and Social Care,
University of Hull, UK
Email: rodtucker.tucker@gmail.com
Actinic keratoses (AKs) are dysplastic keratinocyte lesions confined to the epidermis, which are thought to be induced by excessive exposure to UV radiation. The name is derived from ‘actinic’ – caused by sunlight, and keratosis, which means a ‘thickened scaly growth’. AKs were first described in 1896 by Dubreuilht who appears to have been the first person to distinguish AKs from seborrhoeic keratosis, which are age-related, but benign, lesions.(1)
AKs are most commonly seen in fair-skinned individuals and originate as small, rough spots that are more easily felt than seen; a common analogy is that the affected area feels like sandpaper. The clinical appearance ranges from reddish to red-brown scaly lesions on an erythematous base to a large hyperkeratotic plaque, and the lesions are categorised into one of three grades. Grade 1 represents the ‘felt but not seen’ lesion; grade 2 describes moderately thick, visible lesions; whereas grade 3 denotes very thick, hyperkeratotic lesions.(2)
Typically, AKs appear on sun-exposed areas of the body such as the face, ear lobes and the dorsal surface of the forearm and hands. Patients can develop a single actinic keratosis lesion but more often multiple lesions occur in the same area of skin such as the scalp, a phenomenon referred to as ‘field change’. It has been suggested that within this ‘field’ other sub-clinical lesions are present, some of which have the potential to become malignant and it is recommended that the whole field area is treated.
Prevalence
It has been suggested that AKs could affect 40–60% of adults over the age of 40 years.(3) In the UK, the National Institute for Health and Care Excellence (NICE) has estimated that 19–23% of people over 60 years of age (approximately 2.4–3 million people) have AKs.(4) The prevalence of AKs is higher in men than women and this is likely to be a consequence of the tendency for men to have greater occupational exposure compared with women. Other risk factors for the development of AKs include age and immunosuppression, for example, in transplant patients. Some authorities suggest that AKs are premalignant lesions because there is the potential to develop into both squamous and basal cell carcinoma.
In a study of 7784 high risk patients (that is, those with previously diagnosed keratinocyte carcinomas), it was observed that 65% of squamous cell carcinomas (SCCs) and 36% of basal cell carcinomas (BCCs) arose from clinically diagnosed actinic keratoses.(5) Based on these observations, the authors estimated the risk of progression of AKs to squamous cell carcinoma as 0.60% at one year and 2.57% at four years. The risk of progression to any keratinocyte cancer (that is, squamous or basal cell carcinoma) was estimated at 1.08% at one year and 4.10% at four years. In a more recent analysis, progression of a single lesion to a squamous cell carcinoma for people without immunosuppression was calculated to be between 0 and 0.075% per lesion-year, increasing to a rate of 0.89% per lesion in patients with a previous history of non-melanoma skin cancer,(6) although the authors noted that due to limitations with the evidence, they were unable to give reliable estimates of the rates of conversion.
Although there is the potential for progression to cancerous lesions, AKs can undergo spontaneous remission or remain unchanged. In the review by Werner et al,(6) it was likely that the remission rate of a single AK lesion varied between 15 and 63% per year. Nevertheless, it is impossible to predict the pathway for an individual AK lesion, and because most SCC arise in situ from AKs, treatment is recommended.
Management 
According to guidelines produced by the UK Primary Care Dermatology Society (PCDS), prescribers should first identify high risk individuals with AKs including those with a history of skin cancer and patients who have received phototherapy.(7) The PCDS also recommends that if there are signs that suggest a SCC, patients should be referred using the two-week rule. Additionally, because AKs are caused by cumulative exposure to UV radiation, all patients need to receive sun-protection advice, and there is some evidence that the use of sunscreens slows, but does not prevent, the rate at which new AKs develop.(8) Patients should be informed about the signs and symptoms which might indicate malignant transformation (Box 1) and to promptly report the presence of these changes.
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BOX 1
Signs/symptoms that suggest a squamous cell carcinomas (SCC)
  • Recent growth associated with pain/bleeding
  • An elevated lesion (papule or nodule)
  • Presence of ulceration/induration/tenderness with surrounding inflammation
  • Lesions on the lips which is a common site for SCC
Also consider referral for:
  • Refer young patients due to the possibility of xeroderma pigmentosum
  • Refer immunocompromised patients e.g. post-transplant patients
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Solitary lesions can be managed using liquid nitrogen cryotherapy, which physically destroys the lesion or curettage though this procedure requires a local anaesthetic. Alternatively, AK lesions can be destroyed using photodynamic therapy, which involves the application of a photosensitising agent followed by irradiation of the lesion with a laser.
For patients with field changes, topical therapy is more appropriate since this also targets sub-clinical lesions. Currently there are six topical agents available in the UK as shown in Table 1. Treatment of AKs normally requires several weeks of therapy before improvements are seen which might impact on adherence and in fact a recent study confirmed that as the duration of treatment increased, adherence rates decreased. The study considered 305 patients prescribed any topical therapy for AKs and found that after 3–4 weeks of treatment, 52% of patients were non-adherent, rising to 69% for treatment durations of 4–8 weeks.(9) It seems intuitive, therefore, that any therapy that requires a short duration treatment without sacrificing efficacy would undoubtedly be an advantage in the management of actinic keratosis. One such option is Picato®.
Picato®
In January 2013, Picato® gel was launched in the UK with a maximum duration of treatment of only three days. Two strengths are available: one containing 150mcg/g to treat AKs on the face and scalp, and a stronger preparation (500mcg/g) for use on the trunk and extremities. The lower strength product is applied daily for three days whereas treatment of the trunk and extremities requires two days’ treatment.
Picato® gel contains ingenol mebutate, which is a diterpene ester derived from the sap of Euphorbia peplus (petty spurge), a plant that is commonly found in the UK. The raw sap is released when the plant is damaged and although a skin irritant, the sap has been used for several centuries as a folk remedy for conditions such as warts, basal cell carcinoma and even AKs. In a survey of home remedies for skin cancer and AKs, the sap of was unanimously considered to be effective by users10 and in 2011, a small trial using the sap was conducted in 36 patients with SCCs, BCCs and intra-epidermal carcinoma (IEC). All patients were deemed unsuitable for conventional therapy and treatment involved the application of a small quantity of Euphorbia peplus sap (which contains ingenol mebutate) daily for three days. The results showed that after four weeks, complete clinical response (that is, clearance) rates were 82% (n = 28) for BCC, 94% (n = 16) for IEC and 75% (n = 4) for SCC.(11)
Mode of action
The precise mode of action of Picato® remains unclear but is thought to involve a dual mechanism. Within a few hours of topical application, Picato® induces swelling of mitochondria within dysplastic keratinocytes leading to destruction of these cells via necrosis. Picato® also provokes an inflammatory response which involves infiltration of neutrophils and induction of antibodies so that neutrophils become activated and target any remaining dysplastic epidermal cells. The result is that the neutrophils destroy any remaining dysplastic cells within the field, which helps prevent relapse.(12)
Efficacy
Four clinical trials with over 1000 patients have been conducted with Picato® used either on the face and scalp (547 patients) or trunk or extremities (458 patients). In the studies, included patients had between four and eight clinically discrete grade 1, non-hypertrophic AKs in a 25cm2 contiguous field of skin on the face or scalp or trunk or extremities (for example, hands, arms). Assessment was made on day 57 and the primary outcome measure was complete clearance of all AKs in the treated area or partial clearance, defined as a reduction of 75% or more in the number of clinically visible AKs. The results are summarised in Table 2.
The comparative efficacy of available agents has only been considered in one study, which compared Actikerall® with Solaraze® in 470 patients with AKs on the scalp or forehead. The results showed that complete clinical clearance occurred in 54.1% of patients using Actikerall® and 32% of patients using Solaraze®.(13)
Recurrence of AKs
Recently, the results of a 12-month observational follow-up study of patients who achieved complete clearance of lesions in the initial Picato® trials have been published. For patients who achieved complete clearance of facial or scalp AKs, 46.1% (n = 108) remained clear at 12 months compared with 44%  (n = 76) of patients treated for lesions on the trunk or extremities.(15)
Adverse effects
Treatment of AKs with currently available topical agents gives rise to will predictable local skin reactions (LSRs) that include erythema, scaling/flaking, crusting/scabbing, swelling, vesiculation and ulceration or erosion. In the trials of Picato®, the LSRs peaked between four and eight days after initiation of treatment and were almost resolved on day 15, and by day 29 the skin had returned to normal.(14)
Place in therapy
The lack of comparative trials between Picato® and other available treatments makes it difficult to determine the circumstances under which Picato® would be preferable to other treatments. This lack of comparative studies can be addressed through a network meta-analysis, which is a statistical technique used to simultaneously compare several different treatments and their alternatives. Recently, a network meta-analysis considered eight different therapeutic options for AKs and determined an efficacy ranking based on participant complete clearance.
The analysis concluded that 5-fluorouracil (Efudix®) was the most effective topical agent and that Solaraze® was the least effective, with Picato® ranked as the fourth most effective agent.(16)
Although Efudix® gave rise to greater degree of complete clearance, the short duration of treatment with Picato® (three days compared with four weeks for Efudix®) is likely to promote better adherence. Additionally, the fact that the LSRs experienced by patients receiving Picato® cleared relatively quickly, suggests that Picato® is a potentially valuable addition to the treatment options for the management of AKs.
Key points
  • Actinic keratosis is a common condition affecting up to 60% of people over 40 years of age.
  • Multiple lesions regularly occur in the same area of skin and are best managed with topical therapy.
  • There are currently six topical agents available.
  • Most therapies require several weeks of treatment to be effective
  • Picato® is a recently introduced topical agent which requires only three days of treatment
References
  1. Heaphy MR Jr, Ackerman AB. The nature of solar keratosis: a critical review in historical perspective. J Am Acad Dermatol. 2000;43(1 Pt 1):138–50.
  2. Zalaudek I et al. Morphologic grading and treatment of facial actinic keratosis. Clin Dermatol 2014;32(1):80–7.
  3. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol 1994;131(4):455–64.
  4. National Institute for Health and Care Excellence. ESNM14: Actinic keratosis: ingenol mebutate gel.
  5. http://publications.nice.org.uk/esnm14-actinic-keratosis-ingenol-mebutate-gel-esnm14/estimated-impact-for-the-nhs (accessed 6 March 2014).
  6. Criscione VD et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer 2009;115(11): 2523–30.
  7. Werner RN et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol 2013;169(3):502–18.
  8. Actinic (solar) keratosis. Primary care treatment pathway. PCDS. www.pcds.org.uk/ee/images/uploads/general/Actinic_%28Solar%29_Keratosis_Primary_Care_Treatment_Pathway.pdf (accessed 6 March 2014).
  9. Darlington S et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139(4):451–5.
  10. Shergill B, Zokaie S, Carr AJ. Non-adherence to topical treatments for actinic keratosis. Patient Prefer Adherence 2013;8:35–41.
  11. Green AC, Beardmore GL. Home treatment of skin cancers and solar keratosis. Australas J Dermatol 1988;29(3):127–30.
  12. Ramsay JR et al. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br J Dermatol 2011;164(3):633–6.
  13. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol 2012;66:486–93.
  14. Stockfleth E et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol 2011;165(5):1101–8.
  15. Lebwohl M et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012;366(11):1010–9.
  16. Lebwohl M et al. Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol 2013;149(6):1–5.
  17. Gupta AK, Paquet M. Network meta-analysis of the outcome ‘participant complete clearance’ in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol 2013;169(2):250–9.


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