What’s new in the treatment of premalignant skin disease? Dr Caroline Morgan Poole Hospital NHS Foundation Trust December 3 rd 2015

Why is an update on AK and premalignant skin cancer management needed?

Most actinic keratoses should be managed in primary care GP guidelines to treat AKs and reduce secondary care referrals Guidelines for those AKs to be managed in intermediate care or secondary care There are 3 new topical agents for treating AKs that have been considered at formulary meetings Dorset in the 2 years – and the guidelines get updated frequently!

Fast track referrals

Actinic (solar) keratosis (AK) is a common sun-induced scaly or hyperkeratotic lesion. AK development relates to both constitutional sensitivity to sunlight – i.e. fair skin, inability to tan, and accumulated lifetime exposure. Recent sun exposure will increase number. Regression of AKs occurs when UV exposure decreased, Actinic Keratosis

Distribution represents areas of prolonged sun exposure

Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam Study J.I.D Full body skin check on participants over 45 (mean age 72) AK prevalence 49% for men and 28% for women Male gender, older age, light pigmentation status, severe baldness, skin wrinkling, and high tendency for sunburn were significantly associated with extensive actinic damage (≥ 10 AKs) In the UK affects 1 in 4 people over 60

How does UV cause actinic keratoses? UV damages keratinocyte DNA Abnormal cells destroyed by p53 protein – so preventing them from dividing and proliferating UVB damages P53 gene – doesn’t work properly SCC and AK contain p53 mutations

Normal skin actinic keratosis Proliferation of abnormal keratinocytes at basal cell layer leading to overcrowding and thickening of stratum corneum

AK transformation to SCC -Risk of malignant transformation in any one AK is <1% -The presence of more than ten AK is associated with a 14% risk of developing an invasive SCC within 5 years - and this is increased by continued sun exposure. -Higher rate of transformation seen Immunosuppressed (transplant patients) Lesions on lips (actinic cheilitis) Field change with multiple AK PUVA induced AK

The following could suggest transformation from AK into an SCC: Recent growth / tenderness / inflammation Evidence of induration. Ulceration Lesions resistant to treatments such as cryotherapy Refer urgently to secondary care

Treatment of actinic keratoses Risk for progression of AK to invasive SCC with the potential to metastasis provides the rationale for treatment. AK lesions should be treated with lesion or field – directed therapy or with a combined approach.

Treatment of AK Primary Care Dermatology Society (PCDS) guidelines ary_Care_Treatment_Pathway.pdf Thanks to PCDS for use of images

The majority of patients with actinic keratoses should be treated in primary care

There are a few exceptions…

High risk patients – consider referral to secondary care: –Immunosuppressed patient –Previous history of phototherapy –Young patients (under 35)

Intermediate risk patients – consider referral to GPWSI: –Extensive evidence of sun damage –Past history of skin cancer

Treatment of AK AKs are a marker of sun damage: examine other areas of the skin Encourage prevention: sun screen (factor 30, 4 to 5 star) and protection Advise patients to report change Consider use of emollients for symptom control

Treatment of AK Cryotherapy 5% Fluorouracil - Efudix 0.015% or 0.05% Ingenol Mebutate - Picato 3.75% Imiquimod – Zyclara 5% Imiquimod - Aldara 0.5% Fluorouracil and 10% salicylic acid - Actikerall Curettage and cautery, excision Photodynamic therapy (PDT) (Solaraze removed from formulary in 2014 due to lack of effectiveness)

All topical treatments cause inflammation which indicates their desired action against dysplastic cells. If severe stop treatment. Reassess at 2 weeks to see if further treatment needed at reduced frequency Treatment with zyclara – expected reaction.

Flate erythematous macules with or without scale and possible pigmentation. Often felt easily Treatment options: Cryotherapy Picato Efudix Imiquimod Grade 1 actinic keratosis

Treatment options: Cryotherapy Picato Efudix Zyclara Actikerall PDT Grade 2 actinic keratosis Moderately thick hyperkeratosis on background of erythema that are easily felt and seen

Treatment options: Cryotherapy Curettage and cautery Excision (? SCC) Grade 3 actinic keratosis Very thick hyperkeratosis, or obvious AK, differential diagnosis cutaneous horn

Treatment options: Zyclara Efudix Picato PDT Treating whole area gives advantage of reducing sub clinical lesions so reduces development of further AK Field change Large areas of multiple AKs on a background of erythema and sun damage.

Treatment of AK Cryotherapy 5% Fluorouracil - Efudix 0.015% or 0.05% Ingenol Mebutate - Picato 3.75% Imiquimod – Zyclara 0.5% Fluorouracil and 10% salicylic acid - Actikerall Curettage and cautery / excision Photodynamic therapy What influences treatment decision?

Costs and product licences of individual treatments Table 3 Product name Max skin areaPriceGrade IGrade IIGrade III Field change Liquid nitrogen (cryotherapy)For discrete lesions Costings not available, availability in primary care may be limited.   5% Fluorouracil (Efudix®) Max 500cm 2 area to be treated at any one time (i.e. 23cm x 23cm) 40 g = £32.90   0.5% Fluorouracil and 10% Salicylic acid (Actikerall®) Max 25cm 2 area to be treated at any one time (i.e. 5cm x 5cm) 25 mL = £38.30  Ingenol mebutate (Picato®) Max 25cm 2 area to be treated at any one time (i.e. 5cm x 5cm) 3 x 0.47-g 150mcg/g £ × 0.47-g 500mcg/g, £65.00   Curettage with histologyCostings not available  Photodynamic therapy (with Metvix®) Max 100 cm2 area treated at a time (10cm x 10cm) Costings not available – secondary care only  Imiquimod (Aldara® or Zyclara®) Aldara®, 12 sachet pack = £48.60 Zyclara®, 28 sachet pack = £  Table legend:  = relative recommendation,  = strong recommendation Solaraze removed from formulary due to lack of effectiveness

Cryotherapy Effective – cure rate of up to 98% Patients vary in their tolerance Damages healthy as well as abnormal cells – redness, swelling, pain, permanent loss of pigment and scarring Difficult to treat large numbers of lesions Take care with the lower leg

Cryotherapy freeze times Actinic keratosis 5 to 20 seconds Bowens disease 10 to 20 seconds Superficial BCC 10 to 20 seconds twice (with 2 minute thaw time) Cryotherapy not suitable for nodular BCC Duration of freeze depends on lesion thickness and response to previous cryotherapy

Pitfalls of cryotherapy Expected – oedema and swelling Erythema – use sunscreen to prevent hyperpigmentation Hypopigmentation Secondary infection Inadvertent burn, ulceration Milia Atrophic or depressed scar Avoid cryotherapy on lower leg

Efudix (5 fluorouracil)Efudix (5 fluorouracil) Blocks DNA and RNA synthesis of rapidly dividing cells – cell death Different treatment regimes: –bd for 3/52 –Alternate days for 6/52 –Weekends only for 4/12 Inflammation + + Settles with 1% hydrocortisone cream or ointment – after course of efudix Cure rate 43% to 93% for AK (?compliance)

Phototoxicity Contact Dermatitis Photoprotect for 3 months after treatment – factor 50, 4 to 5 star UVA protection.

Picato (ingenol mebutate) Euphorbia peplus

Picato (ingenol mebutate) Gel topical treatment for AK and field change 2 strengths 0.015% and 0.05% Applied for 3 days to head and neck (nocte) Applied for 2 days to trunk and limbs (nocte) Up to 25cm 2 area treated High compliance – short duration of treatment and simple regime

Picato High compliance 0.015% for face/neck (3 days) 0.05% trunk/limbs (2 days) Do not prescribe topical steroid after treatment Cut open tubes for greater surface area

Picato and superficial BCC Off licence use Marked inflammatory reaction – blistering Works – clearance of superficial BCC on histology

Solaraze / (Diclofenac) Very superficial actinic keratoses and field change Less inflammation than efudix Generally less effective than other agents 1 in 20 get very marked inflammatory reaction Longer treatment regime – b.d. for 90 days No longer on pan Dorset formulary

Imiquimod Aldara (5%) Zyclara (3.75%)

5 % Imiquimod (Aldara) Immune Response Modifier Stimulates the production of interferon, TNF and other cytokines - anti tumour and antiviral activity Tx genital warts, extensive common warts, extensive actinic keratoses, superficial BCC, lentigo maligna (off licence) Apply 5 x week for 6 weeks (sBCC) 3 x week for 4 weeks (actinic keratoses )

Zyclara (3.75% Imiquimod) Field change and grade 1 and 2 AK Treat >25cm 2 Nocte for 2/52, then rest for 2/52 then repeat As with all topical AK treatments the degree of inflammation varies between individuals. Red light in Dorset – high cost!

Actikerall 0.5% Fluorouracil and 10% salicylic acid. Lotion. Efudix – blocks DNA synthesis Salicylic acid - keratolytic For grade 1 and 2 AK Apply od for up to 12 weeks to single lesions Useful alternative to cryotherapy Viral warts

Topical steroid post AK treatment Only effective for efudix, use 1% HC or eumovate Bland emollients such as hydromol or cetraben post picato/imiquimod if needed. Always recommend high factor sunscreen for 3 months post treatment (hyperpigmentation)

Summary of topical AK treatments Efudix b.d. 3 weeks Picato o.d. 2 or 3 days Actikerallo.d. 12 weeks Zyclara o.d.6 weeks (2 weeks off) All treatments can be repeated if necessary Do not use topical steroid after picato or zyclara £33 £65 £38 £113

Treating field change Treat first with a topical agent – Efudix (3 weeks) Picato (3 days) Zyclara (6 weeks) Review patient 1 month after topical treatment finished – treat any persisting individual lesions with cryotherapy

Repeated Treatments Most patients with AK will develop further lesions Clinical judgement as to how frequently to repeat treatments Leave at least 6 weeks post treatment to reassess patient otherwise skin too inflamed.

Photodynamic therapy Bowen’s disease, Actinic Keratoses, Superficial Basal Cell Carcinoma Photosensitising topical ALA (Metvix ) converted to protoporphyrin 9 when irradiated with red light. Releases oxygen free radical leads to cell death. Good for Bowens/sBCC, face, leg, large areas on trunk

Daylight PDT Option for field change (cancerisation) Conventional PDT area treated with blue/red light PDT limited by light source

Curettage and cautery Hypertrophic AK When histology needed to exclude SCC What if is SCC on histology? - usually needs formal excision and follow up.

Actinic cheilitis Cause: chronic UV, chronic lip irritation, smoking. Painless, persistent, usually lower lip More common in men Needs treatment as about 10% progress to SCC

Treatment of actinic cheilitis Efudix Imiquimod Cryotherapy Carbon Dioxide Laser

Bowen’s Disease An intra-epidermal (in situ) squamous cell carcinoma of the skin More common in women The main cause is UVR Patient with fair skin, blue eyes and blond hair are more at risk (skin type I)

Single or multiple Slow growing Sun exposed areas, especially lower legs in woman Appearance –Well-defined pink and scaly patches or plaques. Little substance and finer scale than AK –As lesions grow may become crusty, fissured or ulcerated The rate of transformation into invasive SCC is between 5 and 20% Bowen’s Disease

Treatment of Bowen’s Disease Imiquimod 5/7 for 6 weeks Efudix bd 3/52 Cryotherapy (10 secs) Photodynamic Therapy Curettage and Cautery ? Picato

Keratoacanthoma Develop on sun-exposed skin as single pink papule that grows rapidly over a period of about 12 weeks Dome-shaped lesion with a central keratin core. Start to resolve after 3 months. Best managed as a low-risk SCC and excised as it can be difficult for histopathologists to differentiate between KA and SCC. Refer to Dermatology (Secondary Care – fast track)

Disseminated Actinic Porokeratosis Autosomal Dominant Usually legs/arms >40 Risk of SCC Treatment – efudix, cryotherapy, calcipotriol, acitretin, actikerall. Ineffective! Tx emollients and sunscreen. Manage patient expectations.