Imiquimod 5% Cream (Aldara®) in the Treatment of Basal Cell Carcinoma

M. J. A. Sapijaszko, MD, FRCPC

Department of Medicine, Division of Dermatology, University of Alberta, Edmonton, Alberta, Canada

ABSTRACT

Skin cancer, the most common human cancer, is now a global epidemic. The most prevalent form of nonmelanoma skin cancer is basal cell carcinoma (BCC), the incidence of which continues to increase prompting development of new treatment modalities designed to add or complement current therapies. Although destructive modalities continue to be an important treatment options for BCC, nondestructive measures are a welcome addition to our therapeutic choices. Imiquimod, a topical immune response modifier, belongs to the family of immunostimulators. It enhances both the innate and acquired immune response, and has successfully treated both superficial and nodular basal cell carcinomas through the localized activation of elaborate immune response. Imiquimod can either be used alone or in combination with other treatment modalities. The most common adverse effects of topical use of imiquimod are localized to the site of application and easily managed.

Key Words: imiquimod, basal cell carcinoma, therapy, skin

Skin cancer is the most common human cancer, and nonmelanoma skin cancer (NMSC) is now a global epidemic. BCC accounts for approximately 80% of new cases with superficial (sBCC) and nodular (nBCC) BCCs representing the majority of cases reported. The impact of cutaneous malignancies is significant, since they frequently lead to considerable deformities, either from the disease itself or from the resulting therapy. BCCs can destroy tissue through their relentless local growth. New, less invasive, nonsurgical therapies are welcomed as they may offer treatment without the use of destructive modalities.

The immune system plays an important role in the pathogenesis of NMSC. Immunosuppressed patients, such as organ-transplant recipients, have a greater incidence of BCCs. Regressing BCCs are frequently infiltrated with activated T lymphocytes and cytokines including interferon (IFN)-g, interleukin (IL)-2, and tumor necrosis factor (TNF)-b. Intralesional IFN has been demonstrated to successfully treat BCCs.1

Imiquimod (Aldara™, 3M), a topical immune response modifier, enhances both the innate and acquired immune responses, in particular, the cell-mediated immune pathways,2 and has therefore been studied for the treatment of BCCs.

Mechanism of Action

Imiquimod is a toll-like receptor-7 agonist enhancing both the innate and acquired immune response.3 It activates the production of numerous compounds, including IFN-a, IL-1, -6, -8, -10, -12, and TNF-a, stimulates natural killer cells and the proliferation of B-cells. It also activates Langerhans cells, the key antigen-presenting cell in the skin, and promotes their migration to the regional lymph nodes. Imiquimod stimulates TH-1 cells to produce IFN-g, which in turn can activate cytotoxic T lymphocytes. These cells provide long-term immune memory, which can offer future protection against the previously encountered virus or tumor. In animal models, imiquimod use can establish long-term immunity against viruses and certain tumors.4

Recently, imiquimod has been shown to promote the expression of cellular receptors that are associated with apoptosis.5,6 There is mounting evidence that imiquimod antitumor activity in vivo stems from the effect it has on the innate and cell-mediated immune response, including cell surface markers.

Pharmacokinetics

Imiquimod is applied topically to the affected areas and its clinical effects are primarily localized to the skin. It has minimal percutaneous absorption in healthy skin, the skin of genital warts, and in sun damaged skin. When imiquimod was applied 3 times per week for 16 weeks in 58 patients with actinic keratoses (AKs), the mean peak serum levels at the end of week-16 were very low, measuring approximately 0.1-3.5ng/ml depending whether one packet (12.5mg) was used or up to six packets (75mg) were used. The half-life of topically applied imiquimod is approximately 26 hours with urinary recovery of less then 0.6%.

Clinical Trials

The most common indications for the topical use of imiquimod are the treatment of external anogenital warts, AKs, and sBCCs. In this review, we will concentrate on the evidence for BCC therapy.

In one of the first studies, Beutner and colleagues evaluated the response of BCCs (87% of treated sites were sBCCs) to the topical application of imiquimod.7 The best response (100% histologic clearance) was seen in the b.i.d., q.d. and 3x/week groups. In the first multicenter, randomized, open-label, dose-response trial, 99 patients were randomized to apply imiquimod b.i.d. every day, q.d., b.i.d. 3 times per week, or just once per day, 3x/week for 6 weeks. In an intent-to-treat analysis, the histologic clearance rates were highest in the b.i.d. every day regimen (100%) and lower in the 3x/week regimen (69.7%).8 In a second multicenter, prospective, randomized double-blind, vehicle-controlled study, 128 patients with sBCC were randomized to 12 weeks of imiquimod b.i.d., q.d., 5x/week and 3x/week. Once again, the complete clearance rates varied based on the frequency of drug application from 100% in the b.i.d. group to 51.7 % in the 3x/week group.9

The treatment of nBCC using imiquimod was also assessed with or without occlusion using 6- and 12-week protocols.10,11 Once daily dosing produced the highest clearance rates with 71% and 76% of cancers showing clearance in the 6- and 12-week studies, respectively. Occlusion did not have a clinically significant effect on the treatment of either sBCC or nBCC. The data suggested that a 6-week treatment protocol would be as effective as a 12-week long regimen.

Table 1: Summary of the key published studies assessing efficacy of topical imiquimod in the treatment of basal cell carcinomas.
Abbreviation: Rand – randomized, DB – double-blind, VC – vehicle controlled, OL – open-label, b.i.d. – twice per day, q.d. – once per day, occl – under occlusion

In the two recent double-blind, vehicle-controlled clinical studies, 364 patients with primary sBCCs were treated with imiquimod or vehicle 5 or 7x/week for 6 weeks.12 Twelve weeks following the treatment, histologic clearance rates were 82% and 79% for the 5 and 7x/week groups, respectively. Since the response rates were similar in both groups and the frequency of adverse effects was lower in the 5x/week protocol, the authors recommended that patients with sBCC be treated 5x/week for 6 weeks.
Imiquimod can also be used in combination with other treatment modalities. In particular, it has been studied as an adjunct modality with Mohs surgery,13 electrodesiccation & curettage as well as curettage alone.14

Treating BCC with imiquimod prior to Mohs surgery reduces the size of the tumor and results in a smaller surgical defect. The use of curettage, one of the most common physical treatment modalities, and imiquimod (an immunological agent) allows for the ability to manually debulk the cancer and to ascertain its extent in addition to allowing subsequent application of the topical immune response modifier.

Dosage

The recommended dosing frequency for the treatment of sBCC is 5x/week for 6 weeks prior to normal sleeping hours. In addition to the tumor itself, a 1cm area of normal skin around the tumor needs to be treated. This allows for application to the site of subclinical tumor extensions. When imiquimod is used in combination with curettage, it can be started 1-week postcurettage up to 5x/week and continued for up to 6 weeks. Rest periods can be used as required to manage local skin reactions.

Adverse Effects

Application site reactions, which were the most common adverse effects, were seen in up to 87% of patients treated for sBCCs with imiquimod applied 5x/week for 6 weeks. The most common application site reactions were erythema, edema, induration, erosion, scaling, crusting, pruritus and burning sensations.
Only 2% of patients discontinued the treatment due to the local skin reactions. Some patients may require a rest period if the local reaction severity warrants temporary cessation of treatment. From the clinical point of view, it appears that a patient’s local reaction correlates with the treatment success rate. The incidence of distant reactions, i.e., at sites other than the site of application, is low. Distant reactions include erythema, fatigue, myalgia, arthralgia as well as lymphadenopathy.

Conclusion

Topical, non-invasive, patient-administered modalities continue to expand our options for treating a variety of skin conditions including skin cancers. Less patient discomfort, favorable cosmetic outcome and documented efficacy against BCCs make imiquimod an attractive treatment choice. In addition, patients who are poor surgical candidates (i.e., patients who are elderly, anticoagulated or who have implanted cardiac pacemakers) would benefit from this non-invasive, self-administered topical therapy.
Its usefulness as an adjunct to surgical modalities, such as curettage or surgical excision, allows us to combine immunological- based treatment with surgical intervention.

Imiquimod stimulates innate and cell-mediated immune pathways, which are critical components of the body’s defence mechanisms against both viruses and tumors. The clinical potential of this new family of compounds is growing. What started as a treatment for external anogenital warts has already evolved into an excellent treatment choice for selected skin malignancies.

References

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