Download Update on Management of Actinic Keratoses

What’s new in the treatment of
premalignant skin disease?
Dr Caroline Morgan
Poole Hospital NHS Foundation Trust
December 3rd 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 2009-14
Actinic Keratosis
• 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
• ,
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. 2013
• 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
http://www.pcds.org.uk/ee/images/uploads/general/Actinic_(Solar)_Keratosis_Prim
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
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.
Grade 1 actinic keratosis
Flate erythematous macules
with or without scale and
possible pigmentation. Often felt
easily
Treatment options:
Cryotherapy
Picato
Efudix
Imiquimod
Grade 2 actinic keratosis
Moderately thick hyperkeratosis
on background of erythema that
are easily felt and seen
Treatment options:
Cryotherapy
Picato
Efudix
Zyclara
Actikerall
PDT
Grade 3 actinic keratosis
Very thick hyperkeratosis, or
obvious AK, differential
diagnosis cutaneous horn
Treatment options:
Cryotherapy
Curettage and cautery
Excision (? SCC)
Field change
Large areas of multiple AKs on a
background of erythema and
sun damage.
Treatment options:
Zyclara
Efudix
Picato
PDT
Treating whole area gives
advantage of reducing sub
clinical lesions so reduces
development of further AK
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
Max skin area
Price
Liquid nitrogen (cryotherapy)
For discrete lesions
Costings not available,
availability in primary care may
be limited.
5% Fluorouracil (Efudix®)
Max 500cm2 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 25cm2 area to be treated at
any one time (i.e. 5cm x 5cm)
25 mL = £38.30
Ingenol mebutate (Picato®)
Max 25cm2 area to be treated at
any one time (i.e. 5cm x 5cm)
3 x 0.47-g 150mcg/g £65.00
2 × 0.47-g 500mcg/g, £65.00
Product name
Curettage with histology
Photodynamic therapy (with
Metvix®)
Max 100 cm2 area treated at a
time (10cm x 10cm)
Imiquimod (Aldara® or Zyclara®)
Table legend:
Grade I
Field
change
Grade II
Grade III
PP
PP
P
O
PP
PP
O
PP
P
PP
O
O
PP
PP
O
PP
Costings not available
O
O
PP
O
Costings not available –
secondary care only
O
P
O
PP
Aldara®, 12 sachet pack = £48.60
Zyclara®, 28 sachet pack =
£113.00
P
P
O
PP
P= relative recommendation, PP= 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)
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 25cm2 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 >25cm2
• 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
Picato
Actikerall
Zyclara
b.d.
o.d.
o.d.
o.d.
3 weeks
2 or 3 days
12 weeks
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)
Bowen’s Disease
• 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%
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.