Earliest stage treatment of actinic keratosis with imiquimod 3.75% cream: Two case reports—Perspective for non melanoma skin cancer prevention

Imiquimod 3.75% cream is licensed for the treatment of actinic keratosis (AK). Two case reports on the treatment of facial UV‐exposed skin shall open the discussion if subclinical AKs can be detected by the use of imiquimod cream in UV‐exposed areas even if no lesions can be found clinically. A 87‐year old female showing small scaly AK lesions on her right cheek was treated with imiquimod 3.75% cream. A 59‐year old female without obvious clinical signs of UV‐damage on the face experimentally applied imiquimod 3.75% cream twice daily on the entire face for 2 weeks. In the 87‐year old, inflammatory reaction developed from day 3 onward and showed field cancerization, the lesions healed without scarring. In the 59‐year old at the end of the treatment phase, distinct signs of inflammation appeared, then taking 2 weeks for healing without sequalae. These results open the discussion if the use of imiquimod 3.75% cream could be recommended preventively in UV‐exposed skin areas to obviate a later development of AKs/squamous cell carcinoma/nonmelanoma skin cancer.     

Imiquimod in dermatology: an overview

Imiquimod is an immune response modifier commercially available as a 3.75 and 5% cream. Topical imiquimod stimulates the innate and adaptive immune responses and induces cytokine production. This allows its use for the treatment of a wide variety of benign and malignant skin conditions due to its potential antiviral, antitumor, and immunoregulatory effects. Currently, topical imiquimod is US Food and Drug Administration (FDA)‐approved for the treatment of anogenital warts, actinic keratosis, and superficial basal cell carcinomas. However, it has also shown a beneficial effect in the treatment of many other skin disorders. In this review, we describe existing evidence on the mechanism of action of topical imiquimod, its FDA‐approved indications, off‐label uses, and side effects.     

Efficacy of imiquimod as an adjunct to cryotherapy for actinic keratoses

BACKGROUND: Cryotherapy is the standard of care for clinically apparent (target) actinic keratoses (AKs). Topical imiquimod may reduce initially inapparent or subclinical AKs. OBJECTIVE: We evaluated the potential of topical imiquimod to decrease subclinical AKs after cryotherapy of target AKs. METHODS: A randomized trial of imiquimod or vehicle twice weekly for 8 weeks following 3- to 5-second cryotherapy of target AKs within a 50 cm(2) field at the face or scalp was conducted. Efficacy outcomes included clearance of target, subclinical, and total AKs and proportions clear of AKs. Subjects with residual AKs were offered cryotherapy and open-label imiquimod twice weekly for 8 weeks. RESULTS: Sixty-three subjects completed the randomized phase. At 12 weeks, target AK clearance was similar for imiquimod and vehicle (79% vs 76%), but fewer total AKs were noted for imiquimod (78 vs 116). This was due to a progressive reduction in subclinical AKs with imiquimod compared with a progressive increase with vehicle. More subjects treated with imiquimod achieved clearance of subclinical (58% vs 34%; p = .06) and total (23% vs 9%; p = .21) AKs. CONCLUSION: Imiquimod postcryotherapy may increase clearance of subclinical and total AKs and proportions of subjects clear at 3 months. These findings require confirmation in larger controlled trials powered for statistical significance.     

Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial

Background  Clinical studies in cutaneous conditions other than actinic keratosis (AK) have revealed that the safety and efficacy profile of imiquimod is influenced by dosing frequency.
Objectives  To evaluate dosing frequency response of imiquimod 5% for treatment of AK.
Methods  This was a phase II, multicentre, randomized, double-blind, placebo-controlled study. Adults with ≥ 10 but ≤ 50 clinical AKs, one of which was histologically confirmed, were randomized (4 : 1) to 2–6 packets of imiquimod or placebo cream applied to the dorsum of the forearms and hands once daily 2, 3, 5 or 7 times per week for 8 weeks. The primary endpoint was complete clearance of AKs in the treatment area at 8 weeks post-treatment.
Results  One hundred and forty-nine (94 men and 54 women) white subjects, with a mean ± SD age of 71 ± 10·2 years, were enrolled. Twenty-eight subjects (18·8%) discontinued from study: 0%, 3·1%, 6·9%, 30·0% and 33·3% withdrew for local skin reactions or adverse events in the combined placebo, and in the imiquimod 2, 3, 5 or 7 times per week groups, respectively. Seven serious adverse events occurred; none was related to the study drug. Median baseline lesions ranged from 38 to 40 for the treatment groups. Complete clearance was achieved in 0%, 3·2%, 6·9%, 3·3% and 6·7% of subjects, and partial clearance (≥ 75% lesion reduction) in 0%, 22·6%, 24·1%, 20·0% and 36·7% of subjects for the placebo and imiquimod 2, 3, 5 or 7 times per week regimens, respectively.
Conclusions  Imiquimod 5% applied more frequently than 3 times per week to AKs was not well tolerated. Complete clearance rates were low; however, partial clearance rates increased with increased dosing frequency ( P  =   0·002).     

The role of imiquimod 3.75% cream in the treatment of external genital warts

Imiquimod 3.75% cream has recently been approved by both the U.S. Federal Drug Administration and Health Canada for the treatment of external genital warts. Herein, we provide an overview of external genital warts, review the phase 3 clinical trials leading to the approval of imiquimod 3.75% cream, and compare its efficacy and clinical use with imiquimod 5% cream. Moreover, therapeutic options have further expanded with the relatively recent introduction of sinecatechins 15% ointment, an extract of green tea leaves.     

Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis

BACKGROUND: Actinic keratosis (AK) is the earliest clinical manifestation of squamous cell carcinoma. Metastatic SCC causes the majority of the 1300 to 2300 deaths attributed to nonmelanoma skin cancer in the United States each year. Recent studies have shown that intralesional administration of interferon can be used successfully in the treatment of AK. OBJECTIVE: Imiquimod is an immune response modifier, currently approved for the treatment of genital warts. The topically applied immune response modifier acts by up-regulating interferon and other cytokines involved in the cell-mediated immune response at the site of application. The aim of this was to determine the efficacy and safety of imiquimod 5% cream for the treatment of AK. METHODS: Twenty-two patients with AK lesions were treated with imiquimod 5% cream, initially at 3 times per week for 8 weeks, or until total clearance of lesions. Patients applied imiquimod to lesions on one side of the body and vehicle cream to the other side. A total of 17 patients who completed treatment were evaluated for number of lesions and adverse reactions before treatment and at weeks 2, 4, 6, and 8 after initiation of treatment. AK lesions were also assessed 4 and 8 weeks after treatment. RESULTS: A significant reduction in the average number of lesions per patient was observed for patients treated with imiquimod. The most frequent reactions to treatment were erythema, itching, and scabbing; however, all adverse events were mild to moderate. CONCLUSION: Imiquimod 5% cream may be a promising treatment for AK.     

Open-label study to assess the safety and efficacy of imiquimod 5% cream applied once daily three times per week in cycles for treatment of actinic keratoses on the head

BACKGROUND: Local skin reactions are common during imiquimod treatment of actinic keratosis (AK). Cyclical application of imiquimod may improve tolerability while maintaining efficacy. OBJECTIVE: To assess the tolerability of imiquimod and clearance rate of AK lesions after imiquimod application. METHODS: Imiquimod 5% cream was administered three times per week for 4 weeks followed by 4 weeks of rest (cycle 1) to AK lesions on the head. If AK lesions remained visible at the end of cycle 1, a second treatment cycle was instituted. RESULTS: Fifty percent (30 of 60) of patients experienced complete clearance of AK lesions, and 75% (30 of 40) of patients experienced partial clearance of AK lesions after imiquimod treatment at the end of cycle 2. Moreover, 77% of patients who achieved complete clearance had no visible AK lesions 12 weeks post-treatment. Imiquimod was well tolerated. CONCLUSION: Imiquimod cycle therapy may be a safe and effective treatment option for AK lesions.     

In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma

Background Imiquimod use in the treatment of basal cell carcinoma (BCC) has proven to be successful in a large percentage of cases, inducing tumor regression; however, the exact cellular mechanism has not been fully clarified. Aim To measure the morphological changes in the tumor microenvironment and the markers of apoptosis in skin biopsies from patients with BCC before and after imiquimod treatment. Methods In this open label study, skin biopsies obtained from 11 patients with BCC were evaluated before and after imiquimod treatment for: (i) morphological changes in the tumor microenvironment, with specific emphasis on the immunophenotype of inflammatory cells around the tumor; and (ii) markers of apoptosis, including expression of death receptors. Results Imiquimod treatment induced a significant increase in the mononuclear inflammatory response. In the majority of cases, the cellular infiltrate was predominantly composed of CD3⁺/CD4⁺ T cells, suggesting that the effector response is mediated by CD3⁺/CD4⁺ lymphocytes, with a minor cytotoxic and natural killer (NK) component. An increase in the cytotoxic CD3⁺/CD8⁺ T‐cell population was also observed. Imiquimod treatment was associated with a marked increased in CD20⁺ B cells, and a less pronounced enhancement in cells of monocyte–macrophage origin (CD68⁺) surrounding, or within, the tumor. This finding indicates either that macrophages play a minor role in the imiquimod‐induced response, or the recruitment of these cells is related to time and dose. Imiquimod treatment decreased CD1A⁺ Langerhans cells in the epidermis and increased the number of CD1A⁺ dendritic cells within the tumor aggregates. Imiquimod reduced Bcl‐2 expression, but no difference was found in Bax, Fas/FasL, and p53 expression in BCC cells. Conclusions Our results support the hypothesis that imiquimod activity in the treatment of BCC is partly a result of a pro‐inflammatory action mediated by CD3⁺/CD4⁺ lymphoid cells and of a pro‐apoptotic activity associated with decreased Bcl‐2 expression.     

Pharmacokinetics of imiquimod 3.75% cream applied daily for 3 weeks to actinic keratoses on the face and/or balding scalp

Imiquimod 3.75% cream is a topical formulation of imiquimod intended for daily application to treat actinic keratoses of the entire face or balding scalp. The objective of the study was to characterize serum imiquimod and metabolite pharmacokinetics. Nineteen subjects with actinic keratoses applied two packets of imiquimod 3.75% cream (18.75 mg imiquimod total) once daily for 21 days to a treatment area approximately 200 cm² in size on the face and/or balding scalp. Blood samples were obtained prior to application of doses 1, 7, 14 and 21, and at selected timepoints after application of doses 1 and 21. After multiple dosing (day 21) serum imiquimod mean C _max was 0.323 (standard deviation 0.159) ng/mL, mean AUC(0-24) 5.974 (3.088) ng h/mL, and mean T½ 29.3 (17.0) h. Steady-state was achieved by day 14; multiple dose accumulation ratios were 2.8 based on imiquimod C _max and 3.9 based on AUC. Serum concentrations of imiquimod metabolites were only sporadically quantifiable in three subjects. One subject discontinued from study for adverse events of body aches and fatigue that were attributed to study drug. Treatment-related adverse events occurred in 42.1% (8/19) of the subjects. Systemic imiquimod exposure, as reflected by serum drug concentration, was low after daily application of two packets of imiquimod 3.75% cream for 21 days. Steady state was achieved by day 14, and the observed half-life of approximately 29 h supports daily dosing of the product.     

Psoriasiform Eruption and Oral Ulcerations as Adverse Effects of Topical 5% Imiquimod Treatment in Children: A Report of Four Cases

Abstract: Imiquimod 5% cream is a topical immune‐response modifier indicated in the treatment of multiple cutaneous conditions including actinic keratoses, superficial basal cell carcinoma, and condylomata acuminata. In children, it has been approved only for ages 12 and older in the treatment of external genital and perianal warts. It has also been used off label for a variety of pediatric skin disorders, including molluscum contagiosum (MC), trichoepitheliomas, verrucae plana, and verrucae vulgaris. Local and systemic adverse reactions have been reported, with the most frequently reported events being application site reactions including itching, burning, erythema, and erosion. Although these local reactions are well known, other rare local and systemic reactions can occur. There have been multiple case reports in adults of rare adverse cutaneous reactions occurring with imiquimod, but few have been reported in children. We present four cases of rare adverse cutaneous reactions. In all cases, the children were being treated with imiquimod 5% cream for verrucae or MC. Two of these patients developed a localized psoriasiform eruption, and two developed mucosal ulcerations.     

Immunomodulation by imiquimod in patients with high-risk primary melanoma

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.     

Imiquimod

? Imiquimod, available as a 5% cream, is a new topical treatment for adults with superficial basal cell carcinoma (BCC). The exact mechanism of action of imiquimod in superficial BCC is unknown. Imiquimod may act as a toll-like receptor-7 agonist, and is thought to exert its anti-tumor effect via modification of the immune response and stimulation of apoptosis in BCC cells. ? Topical imiquimod 5% cream effectively increased clinical and histologic clearance of single superficial BCC lesions compared with vehicle in patients enrolled in two large, well designed trials. Patients applied imiquimod five or seven times per week or vehicle for 6 weeks, and the composite clearance rates at 12 weeks post-treatment for the corresponding treatment groups were 75%, 73%, and 2%, respectively. ? In a trial investigating the long-term efficacy of imiquimod 5% cream following application five times per week for 6 weeks, a clinical clearance rate of 90% was reported at the initial 12-week post-treatment examination. The estimated rate of clinical clearance at the 1-year follow-up visit was 84%. ? Application site and local skin reactions were the most common adverse events reported by imiquimod recipients. The severity of erythema, erosion, and scabbing/crusting correlated positively with the composite and histologic response rates.     

Imiquimod: in superficial basal cell carcinoma

Imiquimod, available as a 5% cream, is a new topical treatment for adults with superficial basal cell carcinoma (BCC). The exact mechanism of action of imiquimod in superficial BCC is unknown. Imiquimod may act as a toll-like receptor-7 agonist, and is thought to exert its anti-tumor effect via modification of the immune response and stimulation of apoptosis in BCC cells. Topical imiquimod 5% cream effectively increased clinical and histologic clearance of single superficial BCC lesions compared with vehicle in patients enrolled in two large, well designed trials. Patients applied imiquimod five or seven times per week or vehicle for 6 weeks, and the composite clearance rates at 12 weeks post-treatment for the corresponding treatment groups were 75%, 73%, and 2%, respectively. In a trial investigating the long-term efficacy of imiquimod 5% cream following application five times per week for 6 weeks, a clinical clearance rate of 90% was reported at the initial 12-week post-treatment examination. The estimated rate of clinical clearance at the 1-year follow-up visit was 84%. Application site and local skin reactions were the most common adverse events reported by imiquimod recipients. The severity of erythema, erosion, and scabbing/crusting correlated positively with the composite and histologic response rates.     

Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial

BACKGROUND: Imiquimod 5% cream is a topically applied immune response modifier that has been shown to give effective treatment of actinic keratosis (AK). The therapeutic effects of imiquimod are likely to involve the provocation of a cutaneous immune response against abnormal cells, an assumption based on a strong correlation between complete clearance rates and the severity of the local skin reactions (erythema, oedema, erosion/ulceration, weeping/exudation and scabbing/crusting); however, no clinical studies have conclusively proved this mechanism. OBJECTIVES: To determine the nature of cellular infiltrates induced by the application of imiquimod to AK lesions and to study cells involved in the cutaneous immune response. METHODS: Eighteen patients participated in this phase I, randomized, double-blind, parallel group, vehicle-controlled study. Enrolled patients were randomized in a 2 : 1 ratio to receive imiquimod cream or vehicle cream and applied study cream to five lesions on the scalp, forearm or upper trunk once daily, three days per week for up to 16 weeks. Each patient had punch biopsies of two distinct AK lesions: a lesion was biopsied before treatment to obtain baseline biomarker levels, and a different lesion was biopsied after 2 weeks of treatment. Biopsy specimens were examined using routine and immunohistochemical staining. RESULTS: The imiquimod group showed statistically significant increases from baseline to week 2 in tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86/CD11c, CD68, HLA-DR and TUNEL. No significant differences were seen for the vehicle group. Complete clearance of all treated AK lesions was achieved in five of 11 (45%) imiquimod patients and in none of six vehicle patients. CONCLUSIONS: Imiquimod stimulates a cutaneous immune response characterized by increases in activated dendritic cells and CD4+ and CD8+ T cells.     

Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial

BACKGROUND: Superficial basal cell carcinoma (sBCC) is an increasingly common tumor in fair-skinned populations throughout the world. Imiquimod, an immune response modifier that induces cytokines including interferons, has been shown in preliminary studies to have an effect when applied topically to BCC. OBJECTIVE: We conducted a multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC assessing efficacy and safety of different dose regimens. METHODS: Ninety-nine patients were randomized to 6 weeks' application of imiquimod in 1 of 4 treatment regimens: twice every day, once every day, twice daily 3 times/week, once daily 3 times/week. The treatment site was excised and examined histologically 6 weeks after cessation of imiquimod. RESULTS: Intention-to-treat analysis revealed 100% (3/3) histologic clearance in the twice-daily regimen, 87.9% (29/33) clearance in the once every day regimen, 73.3% (22/30) clearance in the twice-daily 3 times/week regimen, and 69.7% (23/33) clearance in the once-daily 3 times/week regimen. Dose-related inflammatory skin reactions at the site of application were common. The majority were well tolerated and only 1 patient withdrew from the trial as a result of a medication-related skin reaction. CONCLUSION: Imiquimod 5% cream appears to have potential as a patient-administered treatment option in sBCC.     

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe

BACKGROUND: Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream. OBJECTIVES: To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe. METHODS: Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. The target tumour location was identified with an indelible ink mark before treatment initiation. The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation. Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance). Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study. RESULTS: In total, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates. Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively. The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group. CONCLUSIONS: Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream.     

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies

BACKGROUND: Imiquimod is an immune response modifier that is a Toll-like receptor 7 agonist that induces interferon and other cytokines through the innate immune system and stimulates cell-mediated immunity through T cells. Imiquimod has been shown to be efficacious as a topical treatment for basal cell carcinoma (BCC). OBJECTIVE: We sought to evaluate the efficacy and safety of imiquimod 5% cream compared with vehicle for treating superficial BCC (sBCC). METHODS: Two identical studies were conducted. Subjects with one sBCC were dosed with imiquimod or vehicle cream once daily 5 or 7x/week for 6 weeks in these 2 randomized, double-blind, vehicle-controlled Phase III studies. The lesion site was clinically examined 12 weeks posttreatment and then excised for histological evaluation. RESULTS: Data from both studies were pooled. Composite clearance rates (combined clinical and histological assessments) for the 5 and 7x/week imiquimod groups were 75% and 73%, respectively. Histological clearance rates for the 5 and 7x/week imiquimod groups were 82% and 79%, respectively. Increasing severity of erythema, erosion, and scabbing/crusting was associated with higher clearance rates. CONCLUSION: Imiquimod appears to be safe and effective for the treatment of sBCC when compared with vehicle cream. The difference in clearance rates between the two imiquimod dosing groups was not significant. The 5x/week regimen is recommended.     

Imiquimod und die Imidazochinolone: Wirkungsmechanismus und therapeutisches Potenzial

Summary: A central development of the past decade has been in our understanding of the interactions between, and interdependence of, the innate and adaptive immune responses. Innate immunity recognizes “danger” signals and activates adaptive immunity in a targeted, appropriate and effective response. Dendritic cells and macrophages have a central role in this process, and pharmacological agents that modulate the functions of these cells could have therapeutic value. The imidazoquinolone compounds, of which imiquimod, formulated as Aldara?, is the best characterized to date, are such molecules. Imiquimod and its homologues act by activating macrophages and other cells via binding to cell surface receptors, such as Toll receptor 7, thereby inducing secretion of pro‐inflammatory cytokines, predominantly interferon (IFN)‐α, tumour necrosis factor (TNF)‐α and interleukin (IL)‐12. This locally generated cytokine milieu biases towards a Th1 cell mediated immune response with the generation of cytotoxic effectors, and this has been exploited clinically in the treatment of viral infections (human papillomavirus, herpes simplex virus, molluscum contagiosum) and nonmelanoma skin cancer. Imiquimod has been shown to be significantly more effective than placebo in clearing genital warts, and mechanism of action studies indicate that this is related to the ability to generate proinflammatory cytokines and a Th1 response. Intra‐epithelial neoplasms of cutaneous and mucosal surfaces are associated with human papillomavirus infection and there is some evidence that immune response modifiers may have therapeutic value for these lesions. Topical immunotherapy with immunomodulators shows potential for effective and patient‐friendly treatment of cutaneous viral infections. These compounds also have adjuvant properties that could significantly enhance conventional vaccine strategies.