T he most commonly encountered forms of nonmelanoma cutaneous epithelial malignancy include actinic keratosis (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Although not classically included in reported incidence estimates of nonmelanoma skin cancer, AKs are intraepithelial foci of malignancy representing the earliest clinical stage in the continuum of SCC development.1-3 Diagnosed in more than 47 million patient visits in the United States from 1990 to 1999, AK represents about 14% of dermatology visits, with more than 1 million new cases reported annually.1-5 SCCs have been reported in association with one or more AK lesions present in up to 20% of patients, with contiguous
SCC in situ or AK documented in at least 90% of SCCs arising within photodamaged skin.3,5-12 The estimated annual risk of AK progression to invasive SCC has been reported to range from 0.25% to 20%.11 A promising area of therapy for skin cancer is the use of a class of drugs that augment the natural immune response of the skin.

Let’s take an in-depth look at one such drug, topical imiquimod (Aldara). (See “Currently Available Treatment Modalities” on page 46 for other options.) It’s important to understand this drug’s clinical history to get an idea of how it works as an off-label use for skin cancer.

Identification of Imidazoquinolones and Immunomodulatory Effects
In the 1980s, during initial “compound screening” of potential immunomodulator agents, the imidazoquinolone R-837 was shown to inhibit primary and recurrent herpes simplex infection in guinea pig models, associated with marked reduction in viral shedding.21-23 Further testing correlated these effects with induction of cytokine production, corroborated in multiple animal models with both topical and oral administration of R-837. During these preliminary studies, R-837 stimulated production of interferon-alpha (IFN-alpha), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).23 R-837 was shown to induce its effects through stimulation of host immune response, devoid of direct antiviral or cytotoxic activity.22-26 Further study of this compound applied topically in additional animal skin models confirmed upregulation of the local immune response, with enhanced production of cytokines, including IFN-alpha and TNF-alpha.23 Results from numerous studies with topically applied R-837 brought to light additional information on significant immunomodulatory effects, clinical applications, dosage regimens and a favorable safety profile.22,24,26,27

Several analogs of R-837 are under screening and evaluation to determine their potential impact on immunologic upregulation and/or downregulation, including cytokine stimulation patterns, effects on specific cell types (ie. mononuclear cells, dendritic cells, keratinocytes) and receptor ligand interactions.23 Once the “immunomodulation profile” of individual agents is identified, additional research can be rationally matched to specific disease states.

Development of Topical Imiquimod
The compound R-837 is more commonly known to us as topical imiquimod, available in the United States since 1997, and FDA approved as a 5% cream formulation (Aldara) for the treatment of external genital warts. Topical imiquimod is also available in several other countries in Europe, South America and Asia.

In order to better understand the application of topical imiquimod for off label uses, such as epithelial malignancy, background information on treatment of anogenital human papillomavirus (HPV) infection provides an important foundation.

Topical imiquimod has been studied in more than 900 patients in several clinical trials with external genital warts.22 The recommended dosage regimen is three times per week application for up to 16 weeks with an overall complete clearance rate of 50%; median time to clearance has been reported to be 7 to 8 weeks in some studies.22,24,25,27 Reported clearance rates are higher in females (72%) and uncircumcised males (62%) than in the total male patient group (33%), likely related to a greater degree of skin keratinization and lesser degree of natural occlusion in circumcised males.27,28 Low-grade irritation, with erythema, pruritus and occasional focal crusting is anticipated.22-27 This has been termed “cytokine dermatitis,” indicative of the therapeutic host inflammatory response that imiquimod induces. Imiquimod has been shown not to be mutagenic in eight different assays and is classified in pregnancy category B.22

The 16-week duration indicated on product labeling is based on durations used in controlled clinical studies and isn’t “set in stone.” Treatment for up to an additional 16 weeks has proven to be effective and well-tolerated in patients exhibiting either a partial response or recurrence after the initial course of topical imiquimod therapy.27 In patients with partially responsive lesions, the overall clearance rate for the combined initial and extended treatment groups was 90.2% for females and 69.8% for males. In patients exhibiting recurrence after previous cure induced by topical imiquimod, a second course of therapy produced a complete clearance rate of 58.5%.
The potential value of a topical agent for anogenital warts, and other disease states, that is capable of boosting the inherent immune response also suggests benefit for combination therapy with ablative modalities, and reduction in the rate of recurrence due to potential programming of “immunologic memory.” Retrospective analysis completed at one major research center demonstrated a 65% recurrence rate of anogenital warts within an average time period of 5 months in patients treated with surgical removal alone versus 20% recurrence within an average time period of 19 months for patients treated with 16 weeks of topical imiquimod followed by surgical removal of residual lesions.29

Expanded Uses of Topical Imiquimod
The ability of topical imiquimod to facilitate the stimulation of both the innate and acquired immune response provides a unique mechanism of action for the therapy of disease. The concept of enhanced immunologic recognition of a specific disease entity followed by recruitment of a directed immune response opened new avenues for both controlled research and clinical applications.24-27

Clinical trials and case reports have evaluated the use of topical imiquimod and demonstrated efficacy in the management of non-genital veruccae (verruca vulgaris, verruca plana), molluscum contagiosum, keloids, AK, BCC, SCC in situ and Bowenoid papulosis.22,24,27,30-40

Case reports have also documented successful treatment outcomes for several other disease entities including primary limited extramammary Paget’s disease, lentigo maligna, porokeratosis of Mibelli and anogenital warts in children.41-45 Further study is needed to evaluate the role of topical imiquimod in the above mentioned and other cutaneous disorders. Depending on the specific disease state, and pending the outcome of additional research and experience, the clinical application of topical imiquimod may relate to primary and/or adjunctive therapy.

Due to the emergence of literature reporting the efficacy of topical imiquimod for skin diseases other than anogenital warts, off label applications have become a part of the therapeutic armamentarium of several dermatologists. (See the table .)

The therapeutic promise surrounding the development of topical imiquimod is perceived to be the “tip of the iceberg.” Other imidazoquinolone analogs continue to be screened and evaluated to determine their potential for clinical development. R-848 (resiquimod) is currently undergoing clinical investigation for the treatment of genital herpes simplex infection.23

Understanding the Immune Response Facilitation
Additional studies in vitro and in humans have expanded our understanding of the immunologic effects associated with imiquimod. Studies performed with human mononuclear cells and keratinocytes have confirmed induction of multiple cytokines involved in the immune response activation, recruitment, proliferation and effector cell activity.23,24,46 Based on available data, the result of the immunologic effects induced by imiquimod include:
• stimulation of local innate immune activity
• enhanced antigen recognition and migration to regional lymph nodes by dendritic cells such as Langerhans cells
• recruitment of targeted inflammatory cells
• increased activity of acquired cellular-mediated immunity.

The mechanisms involved in the stimulation of innate and acquired immune responses by imiquimod are supported by several investigations. Sequential biopsy specimens from patients treated with imiquimod for warts have identified markers confirming induction of several cytokines including IFN-alpha, IFN-beta, IFN-gamma, TNF-alpha and IL-12.24,44,48 Additional studies inclusive of human mononuclear cells demonstrate that imiquimod induces several other cytokines including IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, IL-12, granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage inflammatory proteins 1-alpha and 1-beta and macrophage chemotactic protein.23-25,46

Pre- and post-therapy evaluations of cellular infiltrates have also confirmed the presence of increased infiltration of cytotoxic T-lymphocytes in patients treated with topical imiquimod for anogenital warts and SCC in situ.38,47 Recent investigations suggest that the activity of imiquimod, at least for the treatment of viral-induced disorders, requires binding with TLR-7, a toll-like receptor ligand present on the surface membrane of certain inflammatory cells including macrophages, monocytes and dendritic cells.23

Application for Cutaneous Epithelial Malignancies
Studies evaluating the tumor immunology of progressively growing BCCs have identified limited detection by normal host immunosurveillance due to a lack of cell surface receptors (LAF-3, ICAM-1) required to bind targeted T-lymphocytes and production by BCC of specific cytokines (ie. IL-4) involved in downregulation of immune response.24,37 These findings are supported by the observation that peritumoral lymphocytic infiltrates surround but do not invade tumor islands.

Intralesional interferon injection has been shown to be effective for the treatment of BCC and SCC.19,20,37 Studies have demonstrated an immunologic state after intralesional interferon similar to what has been identified in association with spontaneously regressing BCC.37 Several cytokines are induced, which enhance expression of BCC surface receptors that allow for binding of activated T-lymphocytes.37,49,50 Interferon also reduces the immune downregulatory response of cytokines secreted by BCC and promotes IL-2 enhancement of cell-mediated activity.37,50

Since topical imiquimod is capable of stimulating a cytokine profile similar to what has been demonstrated with BCC eradication induced by intralesional interferon or spontaneous tumor regression, treatment of cutaneous epithelial malignancy was a rational direction for research and clinical investigation.

Topical Imiquimod and AK Therapy
For the treatment of AKs, the efficacy of topical imiquimod compared to placebo vehicle and the impact on reduction in AK lesion counts have been demonstrated.36,51,52 Evaluations have included AKs of the face, scalp and extremities.34,36,51-54 Two investigations of imiquimod therapy for AK, one case report series (n=6) and one blinded, vehicle-controlled trial (n=36), utilized three times per week application.33,53 In the case series of refractory scalp AKs, application was continued for 6 to 8 weeks; complete clearance was observed clinically and by histologic examination over a follow-up range of 2 to 12 months.33 Patients treated in the larger controlled study continued therapy until clearance of AKs, for a maximum duration of 12 weeks. Clinical and histologic resolution of AKs was achieved in 80% of actively treated patients.53

Due to the development of a more brisk inflammatory reaction (“cytokine dermatitis”) occurring in some patients at regions of drug application, frequency of use was reduced in about 50% of cases, usually to twice a week.36,33,53 The reported cure rates reflect results inclusive of those patients whose therapy was adjusted by reducing the frequency of application. Some patients may benefit from taking short breaks from therapy (1 to 2 weeks) and/or a reduction of frequency to one application per week.36,52 Individual cases of long-term treatment with topical imiquimod twice a week for 9 months for AKs on the hands and forehead have noted continued improvement and maintenance of lesion clearance.34

An open-label, pilot evaluation of “cycle therapy” for AKs involving scalp, cheeks, forehead and temples has been completed with topical imiquimod (n = 25).36,54 A single “cycle” was defined as three applications per week for 4 weeks, followed by a 4-week rest period. At this point, residual AKs were treated with another cycle of therapy; a maximum of three treatment cycles was utilized in the trial. A single cycle evaluated by the end of the 4-week rest period produced clearance in 46% of the treated patients. An additional 36% of patients were responsive to a second cycle of topical imiquimod.

Therapy of BCC and Topical Imiquimod
Several studies using similar protocols have evaluated the efficacy of topical imiquimod in the treatment of BCC, primarily for superficial and nodular subtypes.22-24,37,55,56 A variety of dosing regimens have been assessed. In order to assure the eradication of tumor treated with topical imiquimod, histologic evaluation of excised treatment sites was completed 6 weeks after completion of therapy.37,55,56
• Superficial BCC. Two studies, one open-label (n=99) and one blinded and vehicle-controlled (n=128), compared responses to a variety of dosing regimens using topical imiquimod for treatment of superficial BCC involving the trunk, extremities, neck and face.37,35,57 Imiquimod application three times per week eradicated tumor in approximately 70% of cases. Once daily application in both studies produced nearly identical BCC clearance rates of 87.9% and 87.1%.35,57 In the double-blind trial, it was noted that there was 100% correlation between the histologic confirmation of BCC eradication and the clinical determination by the investigating dermatologist that the tumor was no longer present (100% negative predictive value).57

Currently available data with topical imiquimod for treatment of superficial BCC suggest application five to seven days per week for 6 to 12 weeks.35,37,55-58,59 Six weeks is likely to be sufficient for many patients.
As with treatment of AKs, an inflammatory reaction at the site of application is anticipated. Again, it may be necessary to provide a rest period or alter application frequency in some patients. Overall, the cosmetic results noted after completion of treatment and resolution of associated inflammation were reported to be excellent, with mild residual erythema and hypopigmentation noted in some cases.37 As superficial BCCs are often relatively large in size (>1 cm), are frequently multiple, and involve the trunk in more than 50% of cases, topical imiquimod therapy may be a rational choice to treat the BCC and the surrounding field of actinic damage that is likely to harbor AKs and additional subclinical BCCs.37,60 In addition, the frequent development of broadened or hypertrophic scarring commonly associated with surgery for truncal lesions supports the need for other therapeutic options.

• Nodular BCC. Two parallel trials evaluated multiple regimens with topical imiquimod in the treatment of smaller, nodular BCCs (0.5 cm2 to 1.5 cm2) involving the face, trunk and extremities. Patients were treated with topical imiquimod for 6 weeks (n = 99) in an open study and for 12 weeks in a vehicle-controlled study (n=92).35,37,56,57 Once-daily application (7 days per week) cleared the tumor in 71% in the 6-week study and 76% in the 12-week study. The treated tumors were felt to be of relatively low risk based on histologic pattern, anatomic location and size.56

It’s been suggested that although monotherapy with topical imiquimod may not produce as high a cure rate for nodular BCC when compared to conventional modalities, it may be of benefit in selected clinical situations.37 As superficial BCCs sometimes contain small nodular foci, it’s significant that topical imiquimod has demonstrated efficacy for both superficial and nodular disease.37 Available data suggests that occlusion of topical imiquimod doesn’t appear to significantly enhance efficacy for superficial or nodular BCC, doesn’t allow for effective use of lower dosing frequency, and may unnecessarily increase local skin reactions.37,59,61

SCC In Situ and Topical Imiquimod Therapy
Multiple reports have confirmed the efficacy of topical imiquimod for the treatment of SCC in situ.36,38,39 In the one open trial (n=16), topical imiquimod was applied once daily for 16 weeks. Biopsy of treated areas at 6 weeks after completion of therapy, and clinical follow-up over a 6-month period confirmed 93% clearance of tumor. The age range of treated patients was 60 to 86 years, lesion diameter ranged from 1 cm to 5.4 cm, and more than 90% involved the leg region. In six patients, the development of a marked inflammatory reaction occurred within 4 to 8 weeks of starting therapy, resulting in discontinuation of imiquimod; all patients demonstrated eradication of SCC in situ without further therapy. This suggests that the intensity and/or nature of the targeted inflammatory response plays a major role in inducing a therapeutic effect and may be a more important factor than strict adherence to a specified duration of treatment. Other case reports of SCC in situ have documented efficacy with imiquimod application three times per week for durations ranging from 9 to 17 weeks; post-treatment follow-ups have indicated no evidence of recurrence over a range of 12 to 15 months.62,63 As with therapy for BCC, the overall healing responses and cosmetic results were favorable.

SCC in situ lesions are frequently large in diameter and are sometimes multiple. Anatomic locations that are less amenable to surgery are commonly involved, especially in older patients, including the anterior surface of the legs, scalp and face.36 Based on individual patient-related considerations, the availability of effective and safe medical therapy options, such a topical imiquimod, may be of benefit as monotherapy or adjunctive therapy.

• Combination therapy. Case series have demonstrated efficacy with topical imiquimod for SCC in situ used in combination with oral sulindac (Clinoril) (a cyclooxygenase inhibitor) in immunocompromised patients and with topical 5-fluorouracil in renal transplant patients.64,65

Treatment Tips with Topical Imiquimod
The selection of therapy for AK, BCC and SCC in situ must be made based on considerations of all available treatment options and patient related factors.

• When initiating treatment with topical imiquimod for AK, BCC or SCC in situ, the following recommendations are suggested based on information available to date.

• For the treatment of AKs, initiate therapy with application once a day two to three days per week. The average duration of therapy is 6 to 12 weeks. Cycle therapy (4-week cycle of drug application followed by a 4-week rest peroid) is an alternative approach that may be considered for some patients.

• For therapy of superficial BCC, initiate therapy with application once daily five to seven days per week. The average duration of this therapy is also 6 to 12 weeks.

• For therapy of small, low-risk, nodular BCCs, initiate treatment with application once daily seven days per week for 6 to 12 weeks.

• For therapy of SCC in situ, initiate therapy with application once daily three days per week for up to 16 weeks.

• Occlusion of topical imiquimod is not suggested.

• Drug should be applied to the affected lesion(s) and surrounding skin (1 cm to 2+ cm perilesional zone). Where applicable, based on the extent of involvement with AK, it’s beneficial to treat the entire cosmetic unit. Application prior to bedtime is suggested.

• Patient education regarding the expected development of an inflammatory reaction is very important in order to maximize expectations and enhance compliance.

• Inform patients that the local skin reaction may be low grade in some and brisk in others. Fortunately, patients usually experience only minor local symptoms of irritation, including many patients who exhibit a brisk inflammatory response.

• Educate patients to follow-up earlier if they experience a brisk inflammatory response or discomfort.

• Due to variations in the intensity of the immune inflammatory response (“cytokine dermatitis”), it is difficult to use a stringent “cookbook approach” with imiquimod therapy. The following suggestions for monitoring and treatment adjustment are made based on individual patient responses.

• After initiation of therapy, follow-up with the patient in 2 to 4 weeks to evaluate response.

• Continue current application regimen if only minimal or moderate inflammation is noted.

• If a brisk inflammatory reaction is noted, allow for a short rest period off of therapy (1 to 4 weeks).

• Reexamine at the completion of the rest period. Treatment may be reinitiated by reducing application frequency by 1 day per week.

• Continue follow-up every 2 to 4 weeks until the treatment course is completed. It may be necessary to further alter frequency of application in individual cases.

• In cases demonstrating a brisk inflammatory response, therapy may be individualized based on specific circumstances. Upon careful clinical examination at follow-up, if complete lesion clearance is noted after the visible inflammatory reaction has resolved, the clinician may choose to:

• Reinitiate therapy using a lower application frequency until the course of therapy is completed.

• Stop at this point and follow the patient closely for signs of lesion recurrence. Although histologic confirmation of tumor eradication was a required parameter in some clinical trials, this isn’t a practical consideration in most clinical practice circumstances.

• After completion of a full course of topical imiquimod therapy, the following situations may be present:

• If the treated disease state has resolved, periodic clinical follow-up is recommended.

• For treatment of BCC or SCC in situ, if persistent tumor is still suspected, biopsy is recommended for confirmation of diagnosis. If residual tumor is confirmed, another form of therapy is most likely indicated.

• For treatment of AKs, if persistent or recurrent lesions are noted, additional treatment with imiquimod may be considered if a partial response has been noted. In cases of little to no benefit, another form of therapy is suggested.

A Case Study
A 42-year-old, otherwise healthy, Caucasian female presented with biopsy proven superficial basal cell carcinoma (BCC) of the right upper chest. The lesion was located 1.5 cm medial to a scar resulting from curettage and dessiccation of a previous superficial BCC. On clinical examination, the regional skin around the lesion was actinically damaged, with scattered foci of actinic keratosis (AK) and “salt and pepper” mottled dyspigmentation (Photo 1). The patient voluntarily expressed a strong interest in treatment options other than surgery as she was not pleased with the associated visible scarring. Education regarding consistent long-term photoprotection was presented. Treatment with topical imiquimod was initiated, to be applied once daily seven days per week. She was instructed to apply the drug at bedtime to the lesion and to spread it outward over 2 cm to 3 cm of surrounding skin. The patient was informed to follow-up in 4 weeks and was educated about the likelihood of a local inflammatory reaction.

One month after starting treatment, she presented with a brisk local inflammatory response (Photo 2). She voiced no complaints and on questioning reported minimal irritation. At this point, topical imiquimod was stopped. At follow-up 2 weeks later, minimal erythema was noted and the surrounding skin texture was improved (Photo 3). No additional therapy was administered. Additional follow-up at 5 months after stopping imiquimod demonstrated no evidence of recurrence of superficial BCC, scant residual erythema, slight residual hypopigmentation and no evidence of perilesional AK (Photo 4). The patient reported she was highly satisfied with the results of treatment.