New Medicines Committee Briefing
November 2014
Imiquimod for the treatment of Bowen’s disease (unlicensed indication) and
superficial basal cell carcinoma (licensed indication)
Aldara® (imiquimod 5%) is to be reviewed for use within:
Primary Care

Secondary Care

Summary:
 Basal cell carcinoma (BCC) is a slow-growing, locally invasive malignant epidermal skin tumour mainly
found in Caucasians.
 Bowen’s disease is an intra-epidermal squamous cell carcinoma, which has a rate of transformation into
invasive squamous cell carcinoma.1
 Imiquimod is licensed for the treatment of small superficial basal cell carcinoma (sBCC) and actinic
keratosis (AK) on the face or scalp, all in adult patients.2
 NICE states that topical treatment (e.g. imiquimod) is an option for the management of BCC.3
 British Association of Dermatologists (BAD) in their guidelines noted that the quality of evidence is
strongest for PDT, 5-FU and imiquimod for the treatment of Bowen’s disease and imiquimod 5% cream
has a role in the treatment of sBCC.1,4
 Efudix® is the only licensed topical agent for the treatment of Bowen’s disease in UK.5
 Several RCTs recommend the use of Aldara® for the treatment of both Bowen’s disease and sBCC
 Application site reaction is the most common treatment related adverse event associated with Aldara®
1
Formulary application:
Dermatology:
Consultant submitting application:
Dr Alvin Wong (Consultant Dermatologist)
Clinical Director supporting application:
Dr Gareth Rowland (Clinical Director of Specialised Surgery)
Dr Wong has request that Aldara® be considered for inclusion in the North Staffordshire Joint Formulary for
the treatment of superficial basal cell carcinoma (sBCC) and intraepithelial squamous cell carcinoma
(Bowen’s disease). Aldara® is widely used by dermatologists in the UK and abroad for the treatment of sBCC
and Bowen’s disease. Aldara® is currently licensed for the treatment of AK and sBCC only. However the
British Association of Dermatology recommended imiquimod 5% cream as a treatment option for Bowen’s
disease.
Dr Wong aims to use Aldara® mainly in patients especially elderly in whom surgery and PDT is not a safe
option or not tolerated. He noted his intention of using it also as a second line when there is poor response
to Efudix®
Dr Wong stated in his formulary request that the cost of prescribing Aldara® will be met by reducing
expenditure on surgery and PDT as well as reduction in waiting list for these 2 therapies. He estimates that
around 50 patients per year will be treated with Aldara® (treatment course 6 weeks per cycle).
Background: 6,7,8
Basal cell carcinoma (BCC) is the most common malignancy in white people. Its incidence is increasing
worldwide by up to 10% per year. Although mortality is low as BCC rarely metastasises, this malignancy
causes considerable morbidity and places a huge burden on the healthcare services worldwide. If left
untreated, BCC can cause extensive destruction of tissue especially on the face.
Exposure to ultraviolet radiation is the main causative factor in the pathogenesis of BCC. However, the
precise relation between risk of BCC and the amount, timing, and pattern of exposure to ultraviolet
radiation remains unclear. There are also a number of other risk factors such as skin type 1, red or blond
hair, blue or green eyes, positive family history of skin cancer, current treatment with immunosuppressive
agents and several genetic conditions.
BCCs exhibit several markedly different subtypes and occur at different anatomical locations.
Approximately 80% occur on the head and neck, with the rest mainly on the trunk and lower limbs
particularly in women. Common appearance in early stages is a small translucent or pearly area of skin with
raised areas through which dilated vessels may show. The classic form is the rodent ulcer, which has and
indurated edge and ulcerated centre. It also develops as other patterns such as; nodular or cystic,
superficial, morphoeic and pigmented. BCC is slow growing however, if neglected it can spread deeply to
cause great destruction, especially around the eyes, nose and ears. Even extending into the periorbital
tissues and bone in some cases.
Bowen’s disease is an intra-epidermal squamous cell carcinoma, which has a rate of transformation into
invasive squamous cell carcinoma of approximately 3%. Its aetiology is similar to that of BCC with UV
radiation, fair skin, blue eyes/ blond hair and female patients being at a higher risk. It also has similarity to
2
BCC in its presentation (i.e. single or multiple lesions that are reported to be slow in growing and generally
asymptomatic).
The treatment options for BCC and Bowen’s disease are:
Topical fluorouracil
Topical Imiquimod
Cryotherapy
Surgery often requiring intervention by plastic surgeons.
Photodynamic therapy
Radiotherapy
Laser therapy
Current formulary status:
The North Staffordshire Joint Formulary currently lists the following agents:
13.8
SUNSCREENS AND CAMOUFLAGERS
13.8.1
Sunscreen preparations

Spectraban® (UVB)
Prescriptions in primary care must be endorsed ‘ACBS’
RoC Sante Soleil® (UVB)
Prescriptions in primary care must be endorsed ‘ACBS’
Uvistat® (UVB)
Prescriptions in primary care must be endorsed ‘ACBS’
Photodamage
Solaraze® (diclofenac sodium 3% in sodium
hyaluronate gel)
Efudix® (fluorouracil 5% cream)
2
Restriction: Initiation by a consultant dermatologist or GP with a
special interest
Actikerall® (5-fluorouracil 0.5% and salicylic acid
10% cutaneous solution)
Metvix® (methyl-5-aminolevulinate cream)
Therapeutic class and mode of action: 2
Imiquimod is an immune response modifier. Saturable binding studies suggest a membrane receptor for
imiquimod exists on responding immune cells. Imiquimod has no direct antiviral activity. In animal models
imiquimod is effective against viral infections and acts as an antitumor agent principally by induction of
alpha interferon and other cytokines.
3
Licensed indication:2
Imiquimod cream is indicated for the topical treatment of:
External genital and perianal warts (condylomata acuminata) in adults.
Small superficial basal cell carcinomas (sBCCs) in adults.
Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in
immunocompetent adult patients when size or number of lesions limit the efficacy and/or
acceptability of cryotherapy and other topical treatment options are contraindicated or less
appropriate.
Dosage and administration:2
Superficial basal cell carcinoma in adults:
Apply imiquimod cream for 6 weeks, 5 times per week (example: Monday to Friday) prior to normal
sleeping hours, and leave on the skin for approximately 8 hours. Applied to the lesion and 1 cm
beyond it.
The clinical outcome of therapy can be determined after regeneration of the treated skin, approximately 12
weeks after the end of treatment.
The skin surface area treated should be protected from solar exposure.
Safety and adverse effects:2
Contraindications:
Hypersensitivity to the active substance, lactose or any of the other excipients.
Caution:
Avoid contact with eyes, lips, nostrils, or broken skin, and open wounds; not suitable for internal genital
warts; uncircumcised males (risk of phimosis or stricture of foreskin); autoimmune disease;
immunosuppressed patients
Local skin reactions are common but these reactions generally decrease in intensity during therapy or
resolve after cessation of imiquimod cream therapy. There is an association between the complete
clearance rate and the intensity of local skin reactions (e.g. erythema). These local skin reactions may be
related to the stimulation of local immune response. If required by the patient's discomfort or the severity
of the local skin reaction, a rest period of several days may be taken. Treatment with imiquimod cream can
be resumed after the skin reaction has moderated.
Undesirable effects:
Common: local skin reactions (e.g. itching, burning sensation, erythema, erosion, oedema, excoriation, and
scabbing), headache, influenza-like symptoms and myalgia.
Less common: local ulceration and alopecia
Rarely: Stevens-Johnson syndrome and cutaneous lupus erythematosus-like effect
For additional information refer to the Summaries of Product Characteristics.
4
Drug Interactions:2
Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. This includes studies with immunosuppressive drugs.
Interactions with systemic drugs would be limited by the minimal percutaneous absorption of imiquimod
cream.
Due to its immunostimulating properties, imiquimod cream should be used with caution in patients who
are receiving immunosuppressive medication
Pregnancy and lactation
For imiquimod no clinical data on exposed pregnancies are available. Animal studies do not indicate direct
or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or
postnatal development. Caution should be exercised when prescribing to pregnant women.
As no quantifiable levels (>5 ng/ml) of imiquimod are detected in the serum after single and multiple
topical doses, no specific advice can be given on whether to use or not in lactating mothers.
Special precautions for storage
Do not store above 25°C.
Sachets must not be re-used once opened.
Presentation:2
Boxes of 12 or 24 single-use polyester/aluminium foil sachets, containing 250 mg of cream which is white to slightly
yellow in colour.
Guidance:
NICE Guidance published:9
Yes
NICE Guidance on Cancer Services. Improving Outcomes for People with Skin Tumours including Melanoma
(update): The Management Of Low-Risk Basal Cell Carcinomas In The Community. May 2010
NICE states that there are a range of management options for BCC. NICE recommended that the choice
offered to the patient will depend on the anatomical location, size, clinical appearance, histological
diagnosis and ease of access to treatments and that the ultimate decision should be taken by the patient
having been fully informed about the advantages and disadvantages of management options, including
outcomes in terms of likelihood of complete eradication and cosmetic results.
NICE notes in the guideline the following treatment options after confirmed diagnosis:
Monitoring
Surgical excision
5
Curettage and cautery/electrodessication
Cryotherapy/cryosurgery
Topical treatment ( for example, imiquimod)
Photodynamic therapy (PDT)
Mohns micrographic surgery
Radiotherapy.
Scottish Medicines Consortium (SMC):
No
Aldara® has not been reviewed by the SMC for the use in Bowen’s disease or sBBC.
All Wales Medicines Strategy Group (AWSG)
No
Aldara® has not been reviewed by the AWSG for the use in Bowen’s disease or sBBC.
Regional Drug and Therapeutic Centre (RDTC):
No
Aldara® has not been reviewed by the RDTC for the use in Bowen’s disease or sBBC.
MTRAC
No
Aldara® has not been reviewed by MTRAC for the use in Bowen’s disease or sBBC.
British Association of Dermatologists (BAD)
Yes
BAD guidelines for the management of squamous cell carcinoma in situ (Bowen’s disease) 2014:4
BAD said that many products listed in the guideline do not have license for the treatment of Bowen’s
disease hence all recommendations in the guideline are extrapolated from literature on Bowen’s disease
and knowledge of other neoplastic skin lesions. They stated that choice of therapy will be affected by
patient and clinician access to therapy, patient preference for home-based vs. hospital-delivered therapies,
and therapy cost to the patient and healthcare provider. Standard excisional surgery, curettage and
cryotherapy are widely available for the treatment of Bowen’s disease in secondary care along with the
opportunity to prescribe the topical agents in both primary and secondary care.
6
Imiquimod 5% was recommended for the treatment of Bowen disease, although its licence in the UK is only
for sBBC, AK and genital warts. BAD stated that imiquimod is generally well tolerated, but do cause
significant erythema and crusting hence appropriate counselling needs to be given prior to treatment.
BAD said that the quality of evidence is strongest for PDT, 5-FU and imiquimod, as well as cryotherapy
(often a comparator in trials), which may be influenced by the more rigorous assessment required for
newer therapies seeking regulatory approvals. Surgical excision and curettage remain in common use,
although with lower quality evidence available. They recommended that treatment choice should take into
account evidence of efficacy and tolerability, access to the therapy, cost-effectiveness and patient
preferences.
BAD guidelines for the management of basal cell carcinoma:1
BAD states that topical imiquimod 5% appears to have a role in the treatment of sBCC and gives it strength
of recommendation of A. However it does state that it is currently awaiting results of a 5 year follow up
trail.
The Guideline referred to recent development of more effective topical and nonsurgical therapies which
has increased the treatment options for many low-risk lesions. Despite these, surgery and radiotherapy (RT)
remain the treatments of choice for the majority of high-risk lesions. The Guideline stated that conservative
approach to asymptomatic, low-risk lesions will prevent treatment causing more problems than the lesion
itself. These they noted may be the best option in certain group of patients such as the very elderly, or
those in poor health
Topical immunotherapy with imiquimod is used as a nonsurgical destructive technique for the treatment of
sBCC with several studies reporting its efficacy. Dose–response studies have indicated that the highest
response rates are associated with more frequent or prolonged dosing, together with a significant
inflammatory reaction.
Cochrane Review:
No
Efficacy:
Evidence for Bowen’s disease
1. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s
disease): A randomised, double-blind, placebo-controlled trial10
Patel G et al in a double-blind, placebo-controlled, randomised trial evaluated the efficacy and safety of
imiquimod 5% cream for the treatment of Bowen’s disease. Of the 54 patients recruited for the trial who
on the basis of confirmed biopsy specimen, have Bowen’s disease, only 31 patients met the inclusive
criteria of having at least 1cm2 lesion but no greater than 20cm2. Patients were randomised to either
imiquimod 5% (n=15) or placebo (n=16) to be applied daily to the target lesion for a period of 16 weeks. No
other treatment for Bowen’s disease was allowed. Provision was made for treatment to be stopped after 5
days on two separate occasions in the event of a severe inflammatory episode. Although this did not occur,
7
patients were also given the opportunity to temporarily stop treatment if a third inflammatory episode
warranted it.
Clinical assessments of the targeted lesion for symptoms, erthyema, scale, ulceration, palpability, adverse
events and the response of other cutaneous SCC in situ lesions was conducted at weeks 2, 4, 6, 8, 12 and
16. Response was evaluated by clinical assessment, planimetry, photography and shave biopsy for histology
of the roughest part of the lesion at week 28 and 12 weeks after stopping treatment.
Although the two groups were similar, the mean duration and size of lesion was greater in the imiquimod
group. A total of 3 patients withdrew during the study (all from imiquimod group). 75% (9 patients) of the
imiquimod group achieved complete clinical resolution of the treated lesion compared to none in the
placebo (p<0.001). All the patients that achieved clinical resolution at week 28 did not relapse during the 52
weeks follow up. There was also a significant mean change in lesion area between week 0 and 38 in
imiquimod group (mean = -322mm2, SD = 519mm2) compared to placebo (mean = -37mm2, SD = 114mm2)
(p = 0.041). Histology analysis at week 28 also showed that there was no cutaneous SCC in all cases of
complete clinical resolution.
A treatment related adverse effect common to the imiquimod group was inflammatory response in the
lesional area which ranged in severity from mild transient itching to oedema with erosion and weeping.
These adverse events resolved spontaneously and some with stopping of treatment for up to 5 days. 2
patients were withdrawn because of adverse effect from the study treatment.
2. Imiquimod 5% cream in the treatment of Bowen’s disease and invasive squamous cell
carcinoma11
Peris K. et al in a 16 weeks open-label clinical trial evaluated the efficacy and tolerability of imiquimod 5%
cream on 10 patients for the treatment of Bowen’s disease and invasive SCC in patients unsuitable for
surgery. Patients were considered eligible if they were >18 years of age and considered unsuitable for
surgey because of poor general health status and/or unresponsiveness or contraindications to non-surgical
treatments. The invasive SCC patients were only included if they had no regional lymph node involvement.
Patients applied imiquimod 5% cream daily in the evening for 5 consecutive days a week and continued
until tumour was clinically cleared or until 16 weeks of treatment were completed.
Efficacy and safety evaluation were done by physical examination, photographic documentation,
measurement of treated lesions and documentation of local skin reactions as well as adverse events. These
were performed at monthly clinic visits during treatment period.
Efficacy was rated as:
1
complete regression (i.e. clinical disappearance of lesion)
2
partial regression (i.e. > 40% and <100% reduction in tumour size)
3
no response (i.e. <40% reduction in tumour size)
4
worsening (i.e. increase in tumour size from baseline)
Local skin reactions were rated on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Punch
biopsy (4-5mm) were performed before treatment at the most representative site and 4 weeks after
treatment discontinuation.
Of the 10 patients, there were 5 Bowen’s disease and 7 invasive SCCs. All 10 patients completed treatment.
4 of 5 Bowen’s disease lesions (80%) in 4 patients achieved complete regression after 8 -12 weeks of
treatment while 5 of 7 invasive SCCs (71.4%) in 4 patients. Partial regression was achieved in 1 of 5 Bowen’s
disease lesions (20%) and in 2 of 7 invasive SCCs (28.6%) in 2 patients after 16 weeks. The authors noted
8
that prolonged treatment up to 16 weeks did not provide further clinical benefit in the tumours that
showed partial regression. There was no evidence of residual tumour in the successfully treated SCC
lesions when post treatment histopathologic examination was carried out.
Mild to moderate erythema and pruritus, erosion, ulceration, burning and vesicle formation were local
adverse effect noted though they did not require discontinuation of treatment or drug holidays. There was
also no recurrence after a follow-up period of 24-36 months.
3.
Treatment of Bowen’s disease using a cycle regimen of imiquimod 5% cream12
Chen K and Shumack in case studies reported two patients with Bowen’s disease of the lower limbs who
were successfully treated with imiquimod 5% cream using a cycle regimen. The regimen comprised of
application of imiquimod 5% cream 3 times weekly for 3 weeks, followed by a rest period of 4 weeks.
The authors reported that for the 1st patient, at the end of 1st treatemtn cycle, the lesion had improved but
was not clinically clear. Patient underwent a second cycle and the repeat biopsy at the end of this
treatment showed a complete resolution of the Bowen’s disease. Patient remained clinically clear at the
second month follow-up visit post treatment.
Second patient was a 64 year old white female who had previous treatment which included excision of a
small patch of Bowen’s disease on her lower left leg the previous year. She applied imiquimod 5% cream 3
times a week for 3 weeks and had a 4 week rest period. There was a treatment area improvement but
there was evidence of residual Bowen’s disease. This led to her second cycle and a repeat biopsy showed
mild residual Bowen’s disease with mild nuclear atypical and slight atypical keratinocytes. Another biopsy 2
weeks post treatment showed complete resolution and at 3 months follow-up visit, the treatment site
remained clinically clear.
The authors noted that optimal management (i.e. clearing the Bowen’s disease) can be achieved with
minimal, well tolerated local skin reaction since the severity of local skin reactions with imiquimod tends to
relate to the dosing regimen. They noted that that the rest period allowed any local skin reactions to
subside.
Evidence for treatment of sBCC
1
Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III,
randomized, vehicle-controlled studies13
Geisse J. et al evaluated the efficacy and safety of imiquimod 5% cream in two identical multicentre,
randomised, double-blinded, vehicle-controlled, dose-response, phase III trials for the treatment of sBCC.
The trial involved treating patients with imiquimod or vehicle cream once daily for 5 or 7 times in a week
for 6 weeks. Eligible patients underwent punch or shave biopsy 2-4 weeks prior to initiation visit. Subjects
were randomised to any of the 1 - 4 treatment group and returned to clinic for assessment at treatment
weeks 1, 3, 6, post treatment weeks 4 and 12. A 4-point rating scale was used to assess for local skin
reactions at initiation and post treatment visits. Patients applied a small drop of study cream to a single
target sBCC once daily prior to bedtime according to their assigned treatment regimen for 6 weeks.
The primary efficacy variable was the complete clearance rate defined as the proportion of subjects at
week 12 post treatment visit who were complete responders to treatment. Complete responder was
defined as a subject with no clinical evidence of BCC and no histological evidence of BCC at the target lesion
site. 724 subjects enrolled to the 2 trials with 32 discontinuing during the treatment period and 13 post
9
treatment period. 5 times a week cohort had 185 patients treated with imiquimod and 179 treated with
placebo. 7 times a week cohort had 179 patients on imiquimod and 181 patients on placebo. Compliance
was lower in the 7x/week imiquimod group (81%) than in the imiquimod 5x/week group (91%) and
combined placebo group (97%). Rest periods were considered as missed doses. 7x/week imiquimod and
5x/week imiquimod groups had 22% and 10% rest periods respectively while one subject has rest period in
the placebo group.
The composite clearance rates (combined clinical and histological assessments) for the 5 and 7×/week
imiquimod groups were 75% (95% CI: 68-81%) and 73% (95% CI: 66-79%), respectively. Histological
clearance rates for the 5 and 7×/week imiquimod groups were 82% and 79%, respectively. Increasing
severity of erythema, erosion, and scabbing/crusting was associated with higher clearance rates. There was
a statistically significant difference between each active group and its corresponding placebo group for the
composite and histological endpoints (p<0.001).
Safety:
Higher incidence of adverse events occurred during treatment. 7x/week imiquimod group had higher
incidence of at least 1 adverse event in comparison to 5x/week and combined placebo group (64%, 58%
and 36% respectively). The proportion of subjects experiencing application skin reactions during the
treatment period was significantly higher in the 7x/week compared to 5x/week group (p=0.027). The most
common application reactions for the 2 active treatment groups were itching at the site (26% and 16%,
p=0.021), burning at the target site (9% and 6%), and pain at the target site (6% and 3%). Local skin
reactions were also more intense in the active treatment groups with highest intensity around week 3 and
falling back to /or below baseline level at week 12 post treatment. The local skin reaction intensity rates in
the imiquimod group were significantly higher compared to their placebo group (p<0.001). Erythema,
oedema, vesicles, erosion and scabbing/crusting were all significantly higher in intensity in the 7x/week
imiquimod group compared to 5x/week group (p<0.05). It was noted by the authors that there was a
statistically significant correlation between clearance rate and the severity of local skin reactions (p<0.05).
This trend was not observed in the placebo group.
The authors concluded that Imiquimod appears to be safe and effective for the treatment of sBCC when
compared with vehicle cream and the difference in clearance rates between the 5xweek and 7x/week
imiquimod dosing groups was not significant (75% composite and 82% histologic; 73% composite and 79%
histologic respectively). Based on these finding the authors recommended the 5×/week regimen.
2
Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind,
randomized, vehicle-controlled study.14
Geisse J. et al in a randomised, double-blind, vehicle-controlled phase II dose-response study explored
various dosing regimens using imiquimod 5% cream for sBCC to find the most effective frequency of dosing
with tolerable side effects. There were 128 patients included in the ITT data and patients were randomised
to receive imiquimod or vehicle in 1 of the 4 dosing regimen (twice daily, once daily, 5 times a week, or 3
times a week) over period of 12 weeks. The tumour was clinically assessed, excised and examined for
histologic evidence of residual sBCC 6 weeks post treatment. Local skin reaction categories were erythema,
oedema, induration, vesicles, erosion, ulceration, excoriation/flaking, and scabbing. A 4-point scale was
used for rating.
10
96 patients were randomised to imiquimod and 32 to the vehicle treatment group. Only 10 patients were
randomised to the twice-daily regimen due to the incidence and severity of reported local reactions in this
regimen. 24 patients from the treatment group withdrew from the study due to local skin reaction (n=13),
application site adverse event (n=4), non-compliance (n=2), personal reason (n=2), lost to follow-up (n=2)
and and laboratory abnormality (n=1). Some of the discontinuation was not the choice of patients but
investigators as a result of exceeding the 14 day rest period allowed by the protocol. 41 patients took rest
from study cream application. There were a decreasing percentage of patients taking rests as the dosing
frequency of imiquimod decreased.
There was a positive association between dosing frequency and complete response rate. Higher response
rate was found in patients with more frequency dosing (BD group =100%; OD group = 87.1% [p<0.0001];
5x/week = 80.8% [p<0.0001]; 3x/week = 51.7% [p=0.008] and vehicle = 18.8%).
Safety:
118 patients reported at least 1 adverse event with application site reaction being most frequently (BD =
80%; OD = 81%; 5x/week = 77%; 3x/week = 55% and vehicle = 25%) reported. Most frequently reported
application site reactions were itching, pain and tenderness. 32 severe adverse events were reported by 25
patients and 6 of these (all in OD group) were considered as probably or possibly related to study drug.
The authors concluded that imiquimod 5% cream was effective in the treatment of sBCC with daily or 5
times a week dosing demonstration higher efficacy results with acceptable safety profiles.
3 Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: Results of a multicentre 6week dose-response trial.15
Marks R. et al conducted a multicentre, randomised, open-label dose-response trial to assess the efficacy
and safety of different dosing regimens over 6 weeks of treatment. 99 patients were randomised to
application of imiquimod 5% in 1 of 4 treatment regimens: BD, OD, BD/3x/week and OD/3x/week. Patients
target tumour was clinically assessed (including treatment compliance, local skin reactions and adverse
event) via visits to the clinic at week 1, 2, 4, and 6. Treatment site excision and examination were done
histologically 6 weeks post treatment.
Patients were enrolled in the BD regimen, 33 patients in the OD regimen, 30 patients in the BD/3x/week
regimen and 33 patients in the OD/3x/week regimen. The BD had a small recruit due to frequent reports of
severe local skin reactions.
100% compliance with the intended dosing schedule was achieved in 60 patients. 60% of the scheduled
application was achieved in 93 patients. There was again positive association between dosing frequency
and complete response rate (BD = 100%, OD = 87.9%, BD//3x/week = 73.3% and OD 3x/week = 69.7%).
At least one adverse event was reported in all 4 dose regimens with application site reaction being the
most frequent. There was also a clear correlation between dose-response and application site reactions
(BD= 100%, OD = 66.7%, BD/3x/week = 53.3% and OD/3x/week = 51.5%). Local skin reactions occurred in all
4 dose regimen with erythema occurring more frequently. There was a dose response gradient of local skin
reactions (e.g. erythema: BD= 66.7%, OD = 27.3%, BD/3x/week = 13.3% and OD/3x/week = 9.1%).
4.
Topical Imiquimod or Fluorouracil Therapy For Basal And Squamous Cell Carcinoma. A Systematic
Review16
Love WE et al conducted a systematic review to determine clearance rates and adverse effects of topical
imiquimod or fluorouracil therapy in the treatment of non-melanoma skin cancers such as BCC and SCC and
11
to develop recommendations for use of topical imiquimod or fluorouracil. Two of the authors searched the
MEDLINE, CANCERLIT and Cochrane databases independently for prospective, retrospective, and case
studies containing a minimum of 4 subjects and 6month follow-up or post treatment histologic evaluation.
Out of the 30 publications that met the inclusion, 15 studies included data for 1482 sBCCs treated with
imiquimod while 5 studies included data for 98 Bowen disease treated with imiquimod. One study included
data for sBCC with fluorouracil while 5 studies included data for 134 Bowen’s disease treated with
fluorouracil.
Class A studies in the imiquimod treatment of sBCC had 515 patients who were treated at least daily and at
least 5 days per week for 6 to 12 weeks. 81% of patients were histologically free of disease at 6 or 12
weeks. There were 5 years follow-up results in class B study that included 182 patients and 69% of patients
were clinically free of disease at 5 years after application of 5 days per week for 6 weeks.
Four of the 5 studies in the use of imiquimod for the treatment of Bowen disease evaluated once daily
application while one evaluated daily application 5 day per week. The highest reported clearance rate was
88% in a daily application Cass B study for an average of 12 weeks. Long-term follow-up was not available
for any of these studies.
Only one class B study included data for sBCC treated with fluorouracil twice daily for an average of 11
weeks. There was a 90% clearance rate observed 3 weeks after treatment. There was no clinical follow-up.
A class A and class B studies used the same treatment regimen (once daily for 1 week, then twice daily for 3
weeks) and achieved 56% and 48% clinical clearance rates respectively at 12 months. A study that used
twice daily regimen for 8 weeks achieved an 85% clinical clearance with an average 4.6 years of follow-up.
Adverse effects
Imiquimod: Common adverse events reported of imiquimod were erythema, oedema, weeping, pruritus,
permanent hypopigmentation, crusting/scabbing/scaling, erosion, burning and pain. This led to
discontinuation of treatment in 3% of patients. Intense inflammatory reactions correlated to tumour
clearance rates. Local skin reactions were more intense between 2 to 6 weeks after therapy and erythema
persisted for up to 2 years.
Fluorouracil: Common adverse events reported of fluorouracil were erythema, pain, irritant dermatitis and
pruritus. 5% of patients discontinued treatment as a result of adverse event. There was no correlation
between the intensity of inflammatory reaction and tumour clearance.
The authors recommended topical imiquimod as a consideration for monotherapy only for sBCC and topical
fluorouracil for consideration as monotherapy for sBCC and Bowen’s disease. They noted that the strength
of their recommendation is weak based on level of evidence. They also stated that all their
recommendations are limited to small tumours in low-risk locations in patients who will not undergo
surgery of PDT.
Cost analysis:
Costs of Aldara® in primary and secondary care:
Medicine Description
Aldara cream (Imiquimod 5% cream)
Pack size
Primary Care excl VAT
Secondary Care excl VAT
12 sachets
£48.60
£41.00
12
Cost based on Dr Wong’s estimation
Cost per patient
=
£147.60
Cost per year (est 50 pts)
=
£7, 380.00
Comparative costs for treatment of sBCC and Bowen’s disease:
Cost of course based on UHNS & DT prices (October14)
Course
duration
Medicine Description
Dose
Aldara cream
(Imiquimod 5% cream)
Efudix cream
(Fluorouracil5% cream)
1 application for 5
nights each week
6 weeks
1 application once
or twice daily
3-4
weeks
OPs
required
3 x 12
sachets
2 x 40g
tube
UHNS Price
Cost per
Cost per
tube/pack course incl
incl VAT
VAT
CCG Price
Cost per
Cost per
tube/pack
course excl
excl VAT
VAT
£49.20
£147.60
£48.60
£145.80
£34.40
£68.80
£32.90
£65.80
EXPENDITURE
Expenditure for Sept13-Aug14:
Medicine
UHNS Acute Trust
NORTH STAFFORDSHIRE CCG
STOKE ON TRENT CCG
Aldara cream (Imiquimod 5% cream)
£7,244.59
£2,350.78
£3,878.31
Efudix cream (Fluorouracil5% cream)
£4,019.95
£6,495.09
£4,575.04
References
1
Telfer NR, Colver GB and Morton CA. Guidelines for the management of basal cell carcinoma. British Association of
Dermatologists. British Journal of Dermatology 2008; 159:35-48.
2
Summary of Product Characteristics. Aldara 5%®. Meda Pharmaceuticals. Last Updated on eMC 24/06/10. Available
from: http://www.medicines.org.uk/ <accessed on 16/10/14>
3
National Institute for Health and Care Excellence (NICE). Improving outcomes for people with skin tumours including
melanoma (update): The management of low-risk Basal Cell Carcinomas in the community. May 2010.
4
Morton CA, Birnie AJ and Eedy DJ. British Association of Dermatologists’ guidelines for the management of squamous
cell carcinoma in situ (Bowen’s disease) 2014. British Journal of Dermatology 2014; 170:245-260.
5
Summary of Product Characteristics. Efudix®. Meda Pharmaceuticals. Last updated on eMC 11/03/14. Available via
http://www.medicines.org.uk/emc/medicine/6219 <accessed on 25/10/14>
6
Wong CSM, Strange RC and Lear, JT. Basal cell carcinoma. Clinical Review. British Medical Journal (BMJ). Vol 327, Oct
2003; 794-798
7
Primary care Dermatology Society (PCDS). Bowen’s disease. Available at http://www.pcds.org.uk/clinicalguidance/bowens-disease. <accessed on 22/10/14>
8
Wong CSM, Strange RC, Lear JT. Basal cell carcinoma. British medical journal 2003; 327: 7948.
9
National Institute for Health and Care Excellence (NICE). Improving outcomes for people with skin tumours including
melanoma (update): The management of low-risk Basal Cell Carcinomas in the community. May 2010.
13
10
Patel GK, Goodwin R, Chawla M et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in
situ (Bowen’s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2006; 54:1025–32.
11
Peris K, Micantonio T, Fargnoli MC et al. Imiquimod 5% cream in the treatment of Bowen’s disease and invasive
squamous cell carcinoma. J Am Acad Dermatol 2006; 55:324–7.
12
Chen K, Shumack S. Treatment of Bowen’s disease using a cycle regimen of imiquimod 5% cream. Clin Exp Dermatol
2003; 28(Suppl. 1):S10–12.
13
Geisse J, Caro I, Lindholm J et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results
from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50:722–33
14
Geisse JK, Rich P, Pandya A et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a
double-blind, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50:722-733.
15
Marks R, Gebauer K, Shumack S et. Al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma:
results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 2001; 44:807-813.
16
Love WE et al. Topical Imiquimod or Fluorouracil Therapy for Basal and Squamous Cell Carcinoma. A systemic
Review. Arch Dermatology 2009; 145:1431-1438.
Produced by Sr. Maria Chidiamara Njoku
Primary Care/Secondary Care Interface Pharmacist
University Hospital of North Staffordshire
Telephone: 01782 674541
e-mail: [email protected]
Produced for use within the NHS. Not to be reproduced for commercial purposes.
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