Imiquimod cream (Aldara) for superficial basal cell carcinoma
- Early release
- 4 April 2013
- DOI: http://www.nps.org.au/publications/health-professional/nps-radar/2013/april-2013/imiquimod
Imiquimod is an option for the treatment of small, low-risk sBCC when surgery, curettage or cryotherapy are inappropriate.
Imiquimod is associated with short-term clearance rates of about 80–87% that are sustained for up to 5-years' follow-up.
Imiquimod is also useful for the treatment of solar keratoses (SK) but this is not a Pharmaceutical Benefits Scheme (PBS) subsidised indication. Clearance rates for SK are 50%, with recurrences occurring in 25% of people within 16 months.
Mild to moderate local skin reactions are a common product of imiquimod's anti-tumour activity and are associated with clinical clearance of lesions in response to imiquimod therapy.
It is not known how imiquimod compares with surgical excision, as no head-to-head trials have been reported.
There are also few direct comparisons for imiquimod against other treatments and no specific data regarding imiquimod efficacy when other treatments are contraindicated.
Imiquimod has utility for multiple sBCC lesions but there are limited safety data, and efficacy is not consistent across multiple lesions.
Clearance rates diminish when imiquimod is used on large sBCC lesions, and imiquimod has not been evaluated for sBCC and SK lesions located in high-risk sites such as areas of the face, including eyes, nose, mouth or ears, and SK lesions on the hands or forearms.
Imiquimod presents an alternative treatment for sBCC and SK.
Before considering imiquimod for use on sBCCs, assess lesions for prognostic factors that increase the probability of complete clearance.
Excisional surgery has a higher clearance and lower recurrence rate for sBCC than topical treatments. Field treatment for SK must not exceed a treatment area of 25 cm2.
Be aware that local skin reactions are common and reflect the pharmacological effects of imiquimod associated with clearance. Before prescribing, show patients how to apply imiquimod cream and advise on the correct dose required for the prescribed indication.
From 1 July 2013 both the sachet and pump presentations will be PBS listed for treatment of biopsy-confirmed primary (previously untreated) sBCC in patients with normal immune function for whom surgical excision, cryotherapy, or curettage with diathermy are inappropriate and topical drug therapy is required.
The date of the pathology report and name of the Approved Pathology Authority must be provided at the time of application.
There is also a Repatriation Pharmaceutical Benefits Scheme (RPBS) listing for the sachet presentation of imiquimod for primary treatment of histopathologically confirmed sBCC (when other standard treatments are inappropriate and topical drug therapy is required) and for treatment of SK on the face and scalp (when other standard treatments are inappropriate and topical drug therapy is required as field treatment for clinically visible and subclinical lesions).
The maximum quantity is one pack of 12 sachets with one repeat, or two pumps with one repeat.
Imiquimod (Aldara) is an immune response modifier that promotes NF-kappa-B-mediated secretion of pro-inflammatory cytokines, chemokines and other mediators. These immune responses produce cytotoxic effects that are antiproliferative and anti-tumour, with indirect antiviral effects against some viral infections (e.g. human papillomavirus).1
Imiquimod cream (50 mg/g [5%]) is supplied in a pump that contains 2 g of cream, or as single-use sachets that contain 250 mg.2
Imiquimod is approved by the Therapeutic Goods Administration (TGA) for treatment of sBCC, SK and external genital and peri-anal warts (condyloma acuminata).
Imiquimod is only recommended for people aged over 18 years who will comply with the treatment regimen. The safety and efficacy of imiquimod in patients under 18 have not been established.2
The aim for treatment of BCC is to eradicate the tumour in a manner likely to result in a cosmetic outcome that is acceptable to the patient.3 For most BCC lesions the most effective treatment is excisional surgery, which offers the most prognostically reliable control rates with the advantage of a complete specimen for histological confirmation of tumour clearance,3,4 and low 5-year recurrence when complete excision is achieved.5,6 Surgery also delivers good cosmetic results, particularly when excision and wound repair are performed by experienced practitioners.3
Although surgical excision is often the most effective treatment for BCC there are other alternatives, including:
There is a lack of evidence comparing these different treatment modalities.7
Although field treatment for SK lesions on the face and scalp is not a PBS-subsidised indication, imiquimod is TGA approved and RPBS subsidised for this use. SK lesions may require treatment for cosmetic reasons or because of irritation or the potential for progression to cancer.4,8 No data are available assessing imiquimod as a therapy to prevent squamous cell carcinoma (SCC)-related adverse health outcomes. Although SK has the potential to progress to SCC, the risk of progression is low with no way of determining the risk factor for individual lesions.9 As most lesions do not progress and up to 26% of lesions regress spontaneously,10 the decision to treat depends on clinical judgement. Where treatment is provided, most SK lesions are cleared with cryotherapy, 5-fluorouracil (5-FU) cream or surgery.4 For people with multiple SK lesions, field-directed therapies (e.g. topical) are recommended to allow treatment of clinical and subclinical lesions (i.e. those not yet visible) within the treatment area.11
Consider topical treatments when other options are inappropriate or not preferred. In considering the sachet presentation of imiquimod in 2006, the Pharmaceutical Benefits Advisory Committee (PBAC) noted that there are no direct contraindications to surgical excision, cryotherapy and curettage,12therefore the choice of treatment will depend on clinical judgement. For any BCC for which non-surgical treatments are considered, treatment should be compared with surgery when discussing with patients the likelihood of complete clearance and the risk of recurrence.4
Risk of haematoma, infection and wound dehiscence and unacceptable cosmetic outcomes such as deformity, variation in pigmentation, hypertrophic or keloid scarring (especially for lesions of the upper chest and arms) are some of the disadvantages of surgical interventions that may favour other methods.4Other patient-related factors such as general fitness, coexisting serious medical conditions or the use of antiplatelet or anticoagulant medication also influence the choice of treatment.3 Patient choice, local availability of specialised services and the experience of the treating clinician are other factors to be considered.3,4
Imiquimod is an alternative treatment for small primary sBCC.3,4,7,13–15 The safety and efficacy of imiquimod treatment for BCC of nodular or morpheaform histological subtypes have not been established.2 Confirm the diagnosis by skin biopsy before starting treatment with imiquimod.2
Topical treatments are options for treating low-risk lesions,3 while surgery or radiotherapy should remain the standard for high-risk BCC lesions.3,7 Identify low risk of recurrence for individual lesions based on prognostic factors such as:
Control rates diminish with increasing size and depth of lesions such that 5-year overall estimated control rates of 95% are seen for lesions ≤ 2 cm2 but only 88% for lesions 2–5 cm2 in size.4 Large tumours (> 10–20 cm2) are usually deeply invasive beyond the subcutaneous tissue and are difficult to treat.4There are limited data for large sBCC treated with imiquimod. One small open-label trial showed lower clearance rates of 65% (95% confidence interval [CI] 38% to 86%) for larger tumours > 7.25 cm2 compared with 90% (95% CI 78% to 97%) for smaller tumours ranging from 2.0 to 7.25 cm2. 2,16
Multiple lesions may be problematic and should be considered for specialist referral.4 In the only trial involving multiple sBCCs treated by imiquimod, although the overall tumour response was comparable to those in studies of individual lesions, clearance of one tumour was not predictive of a response in all tumours, and some sites (e.g. lower limb) were associated with a lower clearance rate.17 Ensure continuous monitoring of all lesions during follow-up of patients with multiple lesions.
Imiquimod has not been evaluated for the treatment of sBCC lesions located within 1 cm of the hairline, eyes, nose, mouth or ears.2 Higher recurrence rates for BCC have been observed for all treatment modalities in the facial region — especially in proximity to the nose, eyes and ears — compared with non-facial sites.4 In the US and UK, imiquimod is not approved for lesions located on the face.15
Do not use imiquimod to treat an area of SK in excess of 25 cm2 due to the potential to cause local skin reactions (LSRs).2
Imiquimod has not been evaluated for treatment on the eyelids, the inside of the nostrils, ears, or the lip area inside the vermillion border and there are insufficient data to support the use of imiquimod on the hands and forearms. Imiquimod is not recommended for the treatment of SK lesions when there is marked hyperkeratosis or hypertrophy.2
Although not having a PBS-subsidised indication for treatment of external genital and peri-anal warts (condyloma acuminata) in adults, imiquimod is TGA approved for this use. Imiquimod is a common self-applied treatment for external genital warts and may be used as adjunctive treatment to cryotherapy.18
Assess the clinical outcome of imiquimod therapy after treatment following regeneration of the treated area. For sBCC, assess the treated skin at least 6–12 weeks after completion of treatment.2 Longer follow-up periods for some people may be necessary, as persistent residual local effects such as persistent redness can complicate clinical evaluation.19,20
More than 40% of people will develop a second BCC within 3 years, representing a 10-fold increase in risk compared with the general population. Perform biopsy if there is any doubt about residual tumour. If histological evidence of clearance is not available, follow up initially at 3 months and then 6–12-monthly for up to 3 years. Include a full skin check for new lesions as well as inspection of the site of the original lesion at each examination.4
For SK, assess clearance after a 4-week treatment-free period and if any lesions persist repeat treatment for another 4 weeks.2
Imiquimod is not indicated for use on previously treated sBCC and there is no clinical experience in locally recurrent lesions or incompletely cleared lesions.2One study reported definitive outcomes through surgical intervention and suggested practitioners discuss failure rates with patients and recommend surgery for those with persistent lesions.21 The first opportunity for treatment is the best opportunity to achieve cure.4
In a systematic review of randomised controlled trials (RCTs) using indirect comparisons of clinical recurrence at 3–5 years and early treatment failure (measured histologically within 6 months), surgery and radiotherapy were the most effective treatments for BCC, with the lowest failure rates seen for surgery.7 Another large meta-analysis of treatment of 16,066 lesions reported recurrence rates of < 5% for non-morpheaform BCC (< 2 cm2) after surgical excision with margins of 2–5 mm, and an average recurrence rate of 27% when a positive margin was found.6
Recurrence rates for radiotherapy were comparable,4 although a lower 4-year risk of recurrence was reported for surgical excision over radiotherapy in an RCT of treatment of facial lesions.7,22 Surgery is also associated with more favourable long-term cosmetic outcomes than radiotherapy,23 though outcomes can be influenced by the skill of the operator.4
There are few studies with sufficient long-term follow-up and subgroup analysis (e.g. lesion type, size and site, patient, operator differences) comparing the range of treatment options available for BCC.3,7,24 Most studies have been done on low-risk BCCs. Other treatments may have some utility but need to be evaluated against surgery as the gold standard. To date, no head-to-head trials have been reported comparing imiquimod with surgery.7,14 One RCT is ongoing.25
In a pooled analysis of early (within 6 months) histologically confirmed failed treatment of BCC lesions, there were significantly fewer treatment failures for lesions treated with imiquimod than for those treated with vehicle-control cream (risk ratio 0.25, 95% CI 0.19 to 0.32).7 The analysis included five RCTs for imiquimod,19,26-29 although two of the trials included nodular BCC lesions, which are associated with more modest control rates7. For sBCC vehicle-controlled trials alone, the reported recurrence rate for standard once-daily imiquimod treatment 5 or 7 days per week for 6 weeks ranged from 13% to 20%.19,27,28Lesions were 0.5–2 cm2 in size and located on the neck, face, forehead, upper extremity, trunk or lower extremity. A more recent meta-analysis considering 15 randomised and non-randomised trials (uncontrolled and vehicle-controlled) comprising 1088 sBCC lesions showed an overall recurrence rate of 14% (95% CI 10% to 18%); however, significant heterogeneity was reported, likely due to inclusion of a range of treatment and dosing schedules.24
Imiquimod has a role in treating small primary sBCC although sustained tumour clearance has not been established for imiquimod treatment, with relatively few studies considering clearance rates beyond 1 year. Two open-label, 5-year follow-up studies reported estimated sustained clearance rates, and overall estimated proportion of patients in whom lesions clinically cleared and remained clear, in the range of 85% to 87% and 78% to 80%, respectively, with more than 70% of recurrences occurring within the first 2 years.20,30
Several recent meta-analyses demonstrate that, compared with placebo, imiquimod is an effective therapy for complete clearance of SK lesions located on the face and scalp within treatment areas up to 25 cm2.8,31,32 In one pooled analysis of five randomised double-blind trials involving 1293 patients, complete clearance occurred in 50% of patients treated with imiquimod compared with 5% for vehicle-control, with the secondary outcome of partial clearance (> 75%) reported in 65% of patients in the imiquimod group, compared with 11% for vehicle-control.32 The studies included involved treatment with one sachet of imiquimod cream two or three times per week for 12–16 weeks. 33-37 Higher clinical clearance rates have been observed using imiquimod; however, these were in clinical trials in which the size of the treatment area was greater than the recommended 25 cm2.38
Subclinical lesions may become apparent in the field of treatment during imiquimod therapy. In clinical studies, higher clearance rates were seen for patients with an increase in lesion count relative to the number of SK lesions present at baseline.34,35,37 Recurrence rates of 25% within the treatment area have been reported for three doses per week after a median of 16 months.39,40There are limited long-term recurrence data beyond 16 months. There are also few data comparing imiquimod with other topical agents or treatment modalities. Imiquimod is reported to be of similar efficacy to cryotherapy and 3% diclofenac (in 2.5% hyaluronic acid)8; however, more studies are needed to confirm its non-inferiority to 5-FU.8,41
Dose–response effects for imiquimod treatment have been investigated in several trials comparing treatments ranging from once or twice daily dosing to 3, 5 or 7 days per week.26,27,29,42 In a pooled analysis comparing higher- and lower-dose treatment regimens, a 51% (95% CI 35% to 75%) reduction in histologically confirmed risk of BCC recurrence was reported for higher-dose treatments; however, this was also associated with more LSRs.7 Alternative doses have also been studied for SK involving two or three doses per week in a continuous treatment,34–37 cyclical dosing with a treatment-free period,33,43,44and lower concentration imiquimod creams.45 Lower recurrence was observed in an open-label follow-up study in patients treating SK using three applications of imiquimod per week compared with two.39 Overall, the available data suggest that reducing the dosing frequency does lead to improved tolerability of LSRs but reduces efficacy.
For all indications, imiquimod causes a strong local inflammatory reaction that leads to mild to moderate application-site reactions in most people, and a rest from treatment may be required. In trials, on rare occasions these reactions were accompanied or preceded by systemic flu-like signs and symptoms or exacerbations of inflammatory skin conditions (e.g. dermatitis or psoriasis).2
Report suspected adverse reactions to the TGA online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.
In clinical studies inflammatory reactions to the cream included oedema, redness, erosion, flaking/scaling, skin thickening and scabbing/crusting, which occur in more than 50% of patients being treated for sBCC and SK.2 Other mild skin irritations such as burning, itching and pain were also common for both these indications, and skin infections at the treatment site occurred in about 1% of patients for both sBCC and SK.2 Although common, LSRs are mostly mild to moderate and tolerated by most people.7,14
LSR intensity is highest during the treatment period but subsides to levels at or below baseline during the post-treatment period.19,30,46 With less-frequent dosing, the incidence and severity of LSRs decline.19,29,42 The intensity of LSRs closely relate to imiquimod's anti-tumour activity such that clearance rate rises with increasing intensity of LSRs. Clinical trials have found significant associations between severity of LSRs and clinical clearance rate for sBCC19,29,42,46 and SK.2,34,35,37 Thus an absence of LSRs during imiquimod treatment may be indicative of non-compliance with therapy or a lack of anti-tumour response mechanism,46 and could have utility for predicting which patients will not achieve complete clearance of sBCC.19,46
Advise patients that the LSRs are a normal and expected part of the treatment process and well tolerated by most people.19 Clinical monitoring of LSRs is advised, as complete clearance may be achieved without the presence of erosion, scabbing or crusting,19 and there are instances of failed treatment even when LSRs occurred.21
Treatment schedules for imiquimod reflect a balance between achieving therapeutic efficacy with tolerability of LSRs. A treatment regimen of 5 days/week is recommended for sBCC because of the improved safety profile and similar clearance rates with this dose compared with daily treatment,19 while for SK the recommended treatment schedule is three times per week.2 Higher than recommended doses may lead to increased LSRs.2
The contents of one 250 mg sachet or the amount delivered in one full actuation of the pump may be more than is required for a single application. Advise patients against applying excessive cream to the treatment area and to discard unused cream at each application. In the event of a severe LSR, the cream should be removed by washing the treatment area with mild soap and water. Interruptions in treatment are recommended to allow severe inflammatory reactions to resolve.2 In clinical studies there were few discontinuations due to LSRs, and rest periods were taken around 3–4 weeks after treatment started but occurred as early as the first and as late as the last week of treatment.19,46
For all indications, cases of localised hypo- and hyperpigmentation that may be permanent have been reported after imiquimod use.2 In one long-term follow-up study of sBCCs treated by imiquimod, skin quality changes were most pronounced at 12-week follow-up and 1 year post-treatment and remained stable up to 5 years post treatment.20 During follow-up compared with baseline, hypopigmentation worsened in 48%2 and 57%30 of people, while changes in hyperpigmentation were rare.2,20,30
The safety and efficacy of imiquimod in patients under age 18 have not been established.2 Only use imiquimod in people who are able and willing to adhere to the treatment schedule.
Imiquimod is not PBS listed for use in immunocompromised patients and there is limited clinical experience with use in these patients. Use with caution in organ transplant patients, those with a pre-existing autoimmune or immune deficiency condition or those receiving immunosuppressive medication because of the potential to exacerbate inflammatory conditions of the skin, including graft-versus-host disease.2
Use imiquimod with caution in people with fair skin or those with a high sun exposure.2 People treated with imiquimod may have heightened sensitivity to sunlight and should avoid exposure to sunlight or artificial solar exposure. Do not use imiquimod on sunburned skin until the area is fully recovered. The potential therapeutic effects of using sunscreens simultaneously with imiquimod have not been examined in clinical trials.
Due to an absence of clinical studies do not use imiquimod in pregnant or lactating women.2
The PBAC recommended listing imiquimod 5% cream 2 g multi-use pump on the PBS for the same sBCC indication as the existing single-use sachet. The PBS listing for the sachets was granted on the basis of acceptable cost-effectiveness compared with placebo for patients who cannot have surgical excision, cryotherapy or curettage. The sachets have been PBS listed since 1 December 2006.
The pump presentation is considered interchangeable with the sachets and is suitable for substitution at the point of dispensing.
Imiquimod is available as a multi-use pump or single-use sachet presentation. The maximum quantity is one pack of two pumps available with one repeat, or one pack of 12 sachets available with one repeat. Each pump contains 2 g of cream, of which 1.5 g is available due to the operation of an airless pump system that dispenses about 62 mg per actuation. One pump contains a quantity equivalent to six sachets, and four pump actuations are equivalent to one sachet.2
Ensure patients are provided with the appropriate instructions to match the presentation, as instructions for use differ. The sachets are single use and not intended to be reused after one application. Use the contents of the pump within 4 weeks after opening and discard after this time.2
The treatment area should be washed and dried before applying imiquimod cream to the affected area. A thin layer of the cream should be rubbed into the skin until it is no longer visible. The treatment should be left on for about 8 hours per application (usually overnight) and washed off with mild soap afterwards. Advise patients not to bathe, shower or swim during this time. There is no need to apply an occlusive dressing to the treatment area. Hands should be washed before and after applying the treatment.2
The recommended treatment schedules are as follows:
Advise patients to apply imiquimod sparingly. Four full actuations of the imiquimod pump, or 250 mg of cream, is reported to be sufficient to cover up to 386 cm2 of skin area.47 Therefore, one actuation of the pump (about 62 mg of cream) is in excess of what is likely to be required for a single dose in sBCC and nearly four times the treatable area recommended for SK.
* In practice most clinicians recommend a treatment regimen of 2–3 times a week for 2–4-week cycles.4
Consider rest periods of several days during therapy to resolve or decrease the intensity of severe or intolerable LSRs. In clinical trials, breaks in treatment were reported for 10–19% of patients who missed a median of five prescribed doses.19,46 LSRs decrease in intensity or resolve after cessation of treatment; treatment may resume after the reaction subsides.2 If rest periods are taken, missed doses should not be taken and there is no need to prolong therapy.2 The maximum PBS quantity of one pack of 12 sachets with one repeat or two pumps with one repeat implies that all patients will take a rest period of at least one week during the 6-week course. If a rest is not needed, stop treatment once cream is all used.
Discuss treatment selection for sBCC with patients and inform patients that:
Imiquimod treatment requires an extended treatment period of 6 weeks for sBCC or up to 16 weeks for solar keratosis. When treating with imiquimod, schedule an appointment to review treatment response after 2–3 weeks and discuss how to manage a rest from treatment if local skin reactions become intolerable.
Instruct patients on the proper use of imiquimod cream and refer them to the package insert for further illustrated instructions on how to apply the treatment. For each treatment, patients are advised to:
Refer patients to the Aldara consumer medicine information (CMI) leaflet for more detailed information.
Advise patients of common adverse events and safety precautions associated with imiquimod use. Inform patients as follows.