ABSTRACT

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.

Key Words:
condylomata acuminata, external genital warts, human papilloma virus, HPV, imiquimod, sinecatechins, sexually transmitted infection, STI, topical immunotherapy

External Genital Warts

External genital warts (EGW) have been reported to affect approximately 1.4 million people in the US.¹ More than a half a million new cases develop annually and 10% of all adults will have EGW in their lifetime.¹ The etiology of EGW has been clearly linked to infection with non-oncogenic strains (types 6 and 11) of the human papilloma virus (HPV) transmitted through sexual contact.¹

EGW commonly manifest on fully or partially keratinized skin, such as the penis, vulva, groin, perineum, and perianal areas.² While EGW can be asymptomatic, patients can experience pruritus, dyspareunia, and burning in the anogenital region. EGW can obstruct the urethral orifice and vagina, and impede normal activity. Additionally, large warts can cause obstruction of the anus and rectum.³

Besides physical pain and discomfort, EGW can cause complicated psychological morbidity. Since the disease targets areas of the genitalia and carries the psychosocial stigma of being a sexually transmitted infection, patients can experience a range of emotions, including anger, shame, depression, and low self-worth as potential partners.^4-6 Additionally, the disease can impact the sexual activity of affected individuals, either through actual physiologic pain (in cases of dyspareunia) or through abstinence due to either fear of transmitting to partners or embarrassment of the lesions.⁷ Finally, EGW induces anxiety over treatment efficacy^6,8 and/or recurrences,⁶ as well as the lesion’s potential to develop into a malignancy.⁶ The health and economic burden of EGW is significant, e.g., average number of care days per episode was approximately 96 in 2004.⁹ From 1999 to 2008 the average yearly number of initial physician office visits increased from 240,000 to 385,000.¹⁰

Although EGW spontaneously regresses 30%^2,3 of the time without treatment, there is no way to determine whether a specific lesion will regress, remain unchanged, or increase in size. Treatment should be offered to all patients with EGW resulting from unprotected sexual contact or ineffective prophylactic measures (e.g., condoms, abstinence, or HPV vaccine). Treatment options are available including surgical excision, destructive modalities (e.g., cryosurgery and laser ablation), and topically applied preparations. It is not uncommon for multiple modalities to be used (e.g., excision/destruction with imiquimod). It is outside the scope of this paper to present a cogent review of all therapies, the discussion will instead focus on topically applied imiquimod 3.75%, which received recent regulatory clearance for the treatment of EGW.

Topical Immunotherapy for EGW

Imiquimod 3.75% cream (Zyclara®) is US FDA approved for the treatment of external genital (EGW) and perianal warts – it is marketed in Canada under the trade name Vyloma™ for EGW and Zyclara® for actinic keratoses. Imiquimod, an imidazoquinoline heterocyclic amine, demonstrates antiviral and antitumor properties that are thought to stem, at least in part, from its ability to induce interferon-α as shown in animal studies.¹¹ Specifically, it is an agonist of Toll-like receptor-7 (TLR-7), a member of a pathogen-recognition receptor family.¹² Activation of TLR-7 ultimately enhances antigen-presenting cell activity, migration of Langerhans cells, and cytokine (IFN-α, TNF-α, and IL-1, 6, 8, 10, and 12) release.¹³ Upregulation of IFN-α, β, and γ and TNF-α has a strong association with EGW regression, as well as with a reduction in human papilloma virus DNA and mRNA.^13,14

Elicitation of these immunobiologic changes by imiquimod is not just theoretical. Imiquimod 3.75% was challenged in a clinical study against a vehicle control.¹² Study inclusion criteria required patients to be >12 years of age with 2 to 48 visually diagnosed lesions. The wart size was at least a 6 mm², measured by the two longest axes. The location of the warts included the penis, scrotum, vulva, and inguinal, perineal, or perianal regions. Assessment of treatment was based on number of warts, with a cluster of warts considered as 1 lesion. At each visit, the number of warts was tallied with no differentiation as to whether the lesion was a new growth or an older lesion that had decreased in size. The study was conducted for a maximum of 8 weeks or until complete clearance occurred. The primary endpoint of the study was complete clearance by the end of the study. Secondarily, the researchers observed the sustained complete clearance for a 12-week period. This latter parameter demanded the sustained complete clearance in all areas. Of notable mention, it is very possible that new warts arising very close to the end of the study may not have received any treatment. Resultantly, such patients would have failed to meet the primary endpoint of the study.¹²

Overall, the imiquimod 3.75% cream achieved 27% and 29% significant complete clearance in two different studies, compared with 10% and 9% complete clearance in the respective controls. Females, who for the most part exhibited better response over males, showed a significant complete clearance of 37% in the active treatment group compared to females in the vehicle control group, who demonstrated 14% complete clearance. In treated males, 19% achieved complete clearance as opposed to 4% of males in the control group. After a 12-week observation period of patients who had achieved complete clearance, 85% treated with imiquimod 3.75% cream remained clear.¹²

A recent study comparing imiquimod 3.75% with placebo in female EGW patients found similar results.¹⁵ The study group had a mean wart count of 8.7 with the total mean area of 166.3 mm². Patients receiving imiquimod treatment demonstrated superior clearance over placebo; the median time to clearance was 57 days for imiquimod 3.75% compared with 71 days for placebo. Some other interesting variables that may have contributed to a higher complete clearance rate for imiquimod therapy over placebo include non-white patients, ≤7 warts, total wart area ≤150 mm², diagnosis at ≤6 months, and first episode vs. recurrence. The researchers also looked at the ≥75% clearance and found that again imiquimod 3.75% exhibited greater efficacy compared with placebo. However, the sustained clearance during a 12-week follow up was only 60.4% in imiquimod-treated patients vs. 100% in placebo.

How does Zyclara® differ from Aldara®?

Imiquimod 5% cream (Aldara®) has been FDA approved for the treatment of EGW since 1997. While imiquimod 5% is efficacious for EGW treatment, it is associated with localized adverse effects, including erythema, pruritus, burning, and pain. The standard treatment course requires dosing at 3 times weekly for up to 16 weeks, which may discourage adherence to the regimen.¹⁶ Tolerance of burning and itching for close to 4 months in the anogenital areas can be challenging for patients to endure. A compounding complication is the cumbersome number of treatment days per week, potentially contributing to unintentional noncompliance due to forgetfulness, missed dosing, and confusion as to how to proceed when therapy deviates from the prescribed regimen. Treatment complexity can frustrate patients and contribute to premature termination of therapy. This thought process is confirmed by Murphy and Coster, who have noted that long treatment duration and adverse affects have been associated with decreased compliance.¹⁷ In addition, they suggest linking treatment times with daily habits as one of the strategies to increase compliance,¹⁷ which can be quite difficult if the regimen is 3 times per week.

Development of imiquimod 3.75% focused in part on increasing tolerability and simplifying the treatment regime. Investigation of the 3.75% formulation was undertaken with the intention of reducing the incidence and severity of local skin reactions commonly associated with imiquimod 5%. The total treatment period for imiquimod 3.75% is 8 weeks¹¹ as opposed to 16 weeks for imiquimod 5% cream.¹⁶ The significantly reduced treatment duration and simplified once-daily application offers a more intuitive dosing regimen that can enhance patient adherence.

Another favorable aspect of imiquimod 3.75% that may encourage treatment compliance is its improved tolerability profile as compared with the 5% formulation. In the phase 3 trials, pruritus only occurred in 3% of all imiquimod 3.75% treated patients and irritation was experienced by 6%.¹² Burning was not listed as an independent parameter.¹² Similarly, Baker et al. reported pruritus in 7.8% of treatment patients and irritation in 5.5%.¹⁵ To put these findings into perspective, in patients treated with imiquimod 5%, pruritus was reported by 32% of female patients and 22% of males; burning was experienced by 26% of female subjects and 9% of males.¹⁶ Therefore, imiquimod 3.75% not only shortens a course of therapy by half, but it also demonstrates increased tolerability and dosing simplicity, thereby encouraging treatment follow-through and optimizing outcomes.

Sinecatechins (Green Tea Extract)

It is appropriate to briefly mention sinecatechins 15% ointment (Veregen®), the first botanical drug product approved by the FDA for the treatment of external genital and perianal warts. It contains sinecatechins, including epigallocatechin gallate, derived from green tea leaves. Sinecatechins 15% ointment is applied 3 times a day for up to 16 weeks.¹⁸ Two randomized, double-blind, vehicle controlled studies of both men and women with EGW reported an overall clearance rate of 54.9%; after 6 weeks of therapy, statistically significant differences in clearance rates were observed in patients receiving active treatment.¹⁸ The 12-week sustained clearance was 93.5% of fully cleared patients. Interestingly, the comparator vehicle group showed a complete clearance rate of 35.4% and a sustained clearance rate of 94.2%.

Insights into the possible mechanism(s) of action of sinecatechins in treating EGW were recently presented.¹⁹ In vitro experiments indicated inhibition of matrix metalloproteinase 1, 2, 7, and 9, as well as 20S proteasome activity. In addition, significant suppression of human epidermal growth factor receptor (EGFR) kinase and partial inhibition of extracellular signal-regulated kinases ERK-1 and ERK-2 were also implicated. Furthermore, suppression of inflammatory mediators COX-1 and COX-2 and the lipoxygenase (LO) 12 and 15 proteins were detected. These pathways are involved in the pathogenesis of HPV infection and epidermal proliferation, thereby leading the author to reasonably conclude that these inhibitory activities confer immunostimulant, antiviral, and antitumor properties to sinecatechins that contribute to EGW clearance.¹⁹

Conclusion

In our opinion, imiquimod 3.75% (Zyclara®/Vyloma™) offers a more tolerable and simplified therapeutic option for EGW patients to adhere to therapy. In addition, the recent US regulatory approval of this agent in a pump dispenser further widens the dosing options (established forms consist of individual packets of Aldara® and generic 5% imiquimod cream), such a vehicle advance can facilitate ease of use, improve patient acceptability, and enhance compliance. A study determining the combined effectiveness of sequential cryotherapy followed by a course of imiquimod 3.75% is warranted, as in clinical practice many patients, if not most, are treated with both modalities.

References

1. Hsueh PR. Human papillomavirus, genital warts, and vaccines. J Microbiol Immunol Infect. 2009 Apr;42(2):101-6.
2. Wiley D, Masongsong E. Human papillomavirus: the burden of infection. Obstet Gynecol Surv. 2006 Jun;61(6 Suppl 1):S3-14.
3. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003 Sep;189(3 Suppl):S3-11.
4. Clarke P, Ebel C, Catotti DN, et al. The psychosocial impact of human papillomavirus infection: implications for health care providers. Int J STD AIDS. 1996 May-Jun;7(3):197-200.
5. Jeynes C, Chung MC, Challenor R. ‘Shame on you’–the psychosocial impact of genital warts. Int J STD AIDS. 2009 Aug;20(8):557-60.
6. Sheppard S, White M, Walzman M. Genital warts: just a nuisance? Genitourin Med. 1995 Jun;71(3):194-5.
7. Voog E, Lowhagen GB. Follow-up of men with genital papilloma virus infection. Psychosexual aspects. Acta Derm Venereol. 1992;72(3):185-6.
8. Persson G, Dahlof LG, Krantz I. Physical and psychological effects of anogenital warts on female patients. Sex Transm Dis. 1993 Jan-Feb;20(1):10-3.
9. Hoy T, Singhal PK, Willey VJ, et al. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009 Oct;25(10):2343-51.
10. Centers for Disease Control and Prevention. STD Surveillance 2008. Table 43. Selected STDs and complications – initial visits to physicians’ offices, National Disease and Therapeutic Index: United States, 1966-2008. Available at: http://www.cdc.gov/std/stats08/tables/43.htm. Accessed: February 28, 2012.
11. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol. 1998 Jan;134(1):25-30.
12. Zyclara® cream, 3.75% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2011.
13. Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol. 2001 Mar;8(2):209-20.
14. Diamantis ML, Bartlett BL, Tyring SK. Safety, efficacy & recurrence rates of imiquimod cream 5% for treatment of anogenital warts. Skin Therapy Lett. 2009 Jun;14(5):1-3, 5.
15. Baker DA, Ferris DG, Martens MG, et al. Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies. Infect Dis Obstet Gynecol. 2011;2011:806105.
16. Aldara® cream, 5% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2010.
17. Murphy J, Coster G. Issues in patient compliance. Drugs. 1997 Dec;54(6):797- 800.
18. Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.
19. Tyring SK. Sinecatechins: effects on HPV-induced enzymes involved in inflammatory mediator generation. J Clin Aesthet Dermatol. 2012 Jan; 5(1):19-26.

Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, USA

ABSTRACT

Skin cancer is the most common human cancer, and is currently considered a global epidemic. Recently, there has been a growing interest in immunomodulators, or upregulators of the immune response, for the treatment and cure of various forms of skin cancer, including melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma, Kaposi’s sarcoma, cutaneous extramammary Paget’s disease, and vulvar intraepithelial carcinoma neoplasia. Strategies to augment the host’s immune response against cancer cells and/or cancer cell antigenicity have been investigated, including recombinant cytokines, immunomodulators, dendritic cell immunization, tumor antigen vaccination, T-cell-based immunotherapy, and gene therapy. Although the current standard of care for most of these cancers includes Mohs micrographic surgery, curettage, and cryo-, laser-, or radiotherapy, immunomodulators are becoming essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy.

Key Words:
skin cancer, melanoma, squamous cell carcinoma, immunomodulators, interferon, imiquimod

Recently, there has been a growing interest in immunomodulators for the treatment and cure of skin cancers. The therapeutic effect of immunomodulators on melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma (CTCL), Kaposi’s sarcoma (KS), cutaneous extramammary Paget’s disease, and vulvar intraepithelial carcinoma neoplasia (VIN) is currently being investigated. Today, immunomodulators are essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy, and there is a growing interest in understanding the safety, mechanisms, and therapeutic effect of immunomodulators on skin cancers.

Interferon

Cutaneous Melanoma

In the United States, adjuvant high-dose interferon (IFN) therapy has become the standard of care for melanomas with a high risk of recurrence, and the FDA has approved the use of IFN-á-2b for the treatment of patients with melanomas thicker than 4mm and patients with lymph node metastasis. An early randomized prospective trial by Creagan, et al. did not find a significant difference between IFN-á-2b treated melanoma Stage I and II subjects vs. untreated controls. Although the experimental group had a longer disease-free survival (median, 17 months for the IFN-á-2b group vs. 10 months for the control group), the difference was notsignificant (p=0.09).¹ However, when Rusciani, et al. evaluated Stage II melanoma IFN-á-2b treated subjects vs. Stage II untreated controls, they found a metastasis rate of 19.6% (10 of 51 treated subjects) vs. 60% (18 of 30 untreated controls) at 3 years followup (p<0.0001), and a metastasis rate of 25% (4 of 16 treated subjects) vs. 63% (12 of 19 untreated controls) at 5 years follow-up (p<0.005). The Stage I melanoma IFN-á-2b treated subjects did not have a significantly different disease progression than the untreated Stage I controls at 3 and 5 years follow-up.²

IFN-á-2b therapy appears to be more effective in patients with lesions that have a poor prognosis. A recent study examined the combination of IFN-á-2b and surgery in high-risk melanoma patients. In this retrospective study of 150 patients, adjuvant high-dose IFN was an effective treatment option for patients with high-risk melanoma (Stage IIC, III) after definitive surgery. The 2-year and 5-year relapse-free survival rates were estimated at 48% and 36%, respectively.³

Basal Cell Carcinoma

The antiproliferative property of IFNs has also been employed in the treatment of patients with low-risk nodular basal cell carcinoma (nBCC) or superficial basal cell carcinoma (sBCC). Basal cell carcinoma (BCC) cells have been shown to express the CD95 ligand (FasL) and CD95 receptor (FasR), whereas the surrounding CD4+ T cells predominantly express FasR. Thus, in IFN treated patients, BCC may regress by FasR–FasL mediated apoptosis.⁴ Intralesional IFN-á-2b at a concentration of 1.5 million international units (IU) used over a 3 to 4-week period has been shown to have an overall success rate of up to 100%.^5,6 However, when used for aggressive forms of BCC, this protocol has resulted in a cure rate of only 27% of treated patients.⁷ Therefore, IFN treatment of BCC remains an alternative only for patients with low-risk nodular or superficial BCC.

Squamous Cell Carcinoma/ Actinic Keratosis

Intralesional recombinant IFN-á-2b has been shown to be effective in the treatment of squamous cell carcinoma (SCC) and actinic keratosis (AK). When IFN-á-2b was administered at a dose of 1.5 million IU three times/ week for 3 weeks to SCC lesions, 33 of 34 (97.1%) lesions showed an absence of SCC histologically.⁸ However, when compared to other treatments for AK, the use of IFN is limited by the pain of injections and the multiple follow-up visits necessary.

Cutaneous T-cell Lymphoma

IFN-a is one of the most effective single-therapy agents for the treatment of CTCL.⁹ Low-grade, nonHodgkin, T-cell lymphomas are always associated with cutaneous involvement and include mycosis fungoides (MF) and the Sézary syndrome (SS).¹⁰ A literature review by Bunn, et al. of 207 MF and SS cases treated with IFN- a-2a revealed an overall response rate of 55%, with 17% of cases being complete responders to IFN-a-2a therapy. These authors concluded that recombinant IFN-á-2a monotherapy has greater benefit in patients with early-stage disease, with 3 million IU of IFN-á-2a given subcutaneously three times/week being the optimal treatment regimen. In this study, no therapeutic differences were observed between IFN-á-2a and -2b.¹¹ A study by Vonderheid, et al. has revealed that intralesional injections of MF plaques with IFN-á-2b at a dose of 1 million IU given three times/week for 4 weeks produces substantial localized clinical and histological improvement with 10 of 12 plaques demonstrating complete regression localized to the IFN-á-2b injected sites.¹²

Kaposi’s Sarcoma

The use of IFN-a-2a and -2b in the treatment of KS in patients with acquired immune deficiency syndrome due to the human immunodeficiency virus has been approved by the US FDA. The recommended dosages for IFN-a-2a and -2b are 36 and 30 million IU subcutaneously three times/week, respectively. The average response rate of KS to high-dose IFN-á therapy has been approximately 30%. In many cases, tumor recurrence has been observed within 6 months after discontinuation of treatment, and response to subsequent treatments has not been reliable. This has led to indefinite treatment regimens until side-effects become intolerable.¹³

Imiquimod

As an immune response modifier, imiquimod induces IFN-á, tumor necrosis factor (TNF)-a, IL-1, IL-6, IL-8, and IL-12 production by monocytes, macrophages and toll-like receptor (TLR)-7-bearing plasmacytoid dendritic cells. TLR-7 is an essential receptor for imiquimodinduced immune responses.¹⁴ Imiquimod also generates production of IFN-a after CD4 cells are stimulated by IL-12. IFN-a stimulates cytotoxic T lymphocytes responsible for killing virus-infected and tumor cells.

Topical imiquimod 5% cream has been found to be effective in the treatment of lentigo maligna (LM, in situ melanoma). In a pilot, open-label, nonrandomized study evaluating the effectiveness of imiquimod 5% cream once daily for a maximum of 13 weeks on five patients with LM, a 100% response rate was observed without reoccurrence during a 3–18 month follow-up interval.¹⁵ Case reports describing multiple metastatic melanoma skin lesions clearing after topical imiquimod 5% cream application have also been published. The two patients studied applied imiquimod 5% cream three times/week to the metastatic skin lesions with a 1cm surrounding margin.¹⁶

Basal Cell Carcinoma

Imiquimod 5% cream has been shown to induce the expression of FasR on BCC cells, and FasR mediated apoptosis may contribute to the effectiveness of imiquimod in BCC treatment.¹⁷ An initial 16-week, dose-ranging, vehicle-controlled trial examining the effect of 5% imiquimod cream on nBCC and sBCC found an overall histological response rate of 83% (20/24) in the 5% imiquimod cream treatment group vs. 9% (1/11) in the vehicle treatment group.18 Subsequent sBCC randomized, multicenter studies have reported 100% efficacy with twice daily application vs. 73–88% efficacy with once daily application of 5% imiquimod cream.^19–21

Squamous Cell Carcinoma/ Actinic Keratosis

Imiquimod studies in SCC patients are restricted to AK and in situ SCC clinical presentations. A 16-week, twice weekly, imiquimod 5% cream treatment regimen has been approved by the FDA for patients with AK lesions on the face or scalp. This treatment regimen has achieved a 45.1% (97/215) complete clearance and a 59.1% (127/215) partial clearance rate. These clearance rates are significantly higher than the complete and partial clearance rates found in the vehicle group (p< 0.001).²²

Bowen’s Disease

Current therapies for Bowen’s disease, or intraepidermal SCC, include 5-Fluorouracil, surgical excision, curettage, electrocautery, cryo-, laser-, photo-, and radiotherapy.²³ In a Phase II open-label study, 16 biopsyproven plaques of Bowen’s disease, with diameters ranging between 1–5.4 cm, were treated once daily for 16 weeks with imiquimod 5% cream. Of the 16 lesions treated, 15 were on the lower extremities and 1 was on the shoulder. Fourteen of 15 patients (93%) had no residual tumor present in the 6-week post-treatment follow-up biopsy. Thirteen patients were followed to 6 months without disease recurrence.²⁴

Extramammary Paget’s Disease

Extramammary Paget’s disease (EMPD) is an infrequent epidermal malignancy most commonly occurring in the anogenital and vulvar regions. Therapeutic modalities
include wide local excision and Mohs micrographic surgery. A case report of two patients with primary limited cutaneous perineal and genital EMPD describes successful treatment of EMPD with imiquimod 5% cream, with confirmation of cure after 7.5–12 weeks of monotherapy. The treatment-associated morbidity was minimal when compared with other more invasive therapies.²⁵ Another case study has documented the eradication of EMPD of the scrotum in a 68-year-old male with nightly application of imiquimod 5% cream for 6 weeks, with no signs of reoccurrence at 6 months after discontinuation of therapy.²⁶

VIN

Imiquimod was preconceived as possibly beneficial in the treatment of VIN of human papilloma virus etiology, due to its antiviral and antineoplastic properties; however, the literature shows mixed results. In a prospective, observational study examining the effects of imiquimod 5% cream three times/week for 16 weeks in 15 patients with high-grade VIN, 3 demonstrated local side-effects, including soreness, burning, erythema, ulceration, and blistering. One patient required hospitalization, catheterization, and analgesia. Of the 13 patients who completed the study, four demonstrated clinical improvement. Of these four patients, only one had a negative VIN biopsy. All four patients who responded clinically relapsed 4 months after treatment.²⁷However, in a recent study examining the effect of imiquimod 5% cream applied three times/week for a maximum of 16 weeks in eight patients with biopsy-proven bowenoid and basaloid, VIN 2/3 had better results. Total clearance and partial clearance was observed in six patients and two patients, respectively, and the post-treatment biopsy showed an absence of precancerous lesions in seven of eight patients (87.5%).²⁸

Dendritic Cell-based Therapy

The use of autologous dendritic cells (DCs) loaded with tumor-associated antigens as a natural adjuvant to actively prime an effective immune response against tumor cells is also being investigated.^29–35 A Phase I clinical trial by Escobar, et al. designed to address the safety and efficacy of immunizations with tumor lysateloaded DCs in Stage III–IV metastatic melanoma patients found a significantly longer post-vaccination survival in patients with a delayed type IV hypersensitivity reaction against the melanoma cell lysate (17.25 months) than in nonresponders (8.625 months), (p=0.0261).³⁶ This study demonstrated that the vaccination procedure used was safe and could induce a clinical and immunologic response in patients with advanced melanoma, like other studies with comparable protocols.^35,37 However, a recent randomized Phase III clinical trial studying the effect of dacarbazine monochemotherapy vs. vaccination with autologous peptide-pulsed DCs in patients with metastatic melanoma found Grade 3/4 toxicities in seven patients in each treatment arm, and a total of 75 deaths at median follow up of 22.2 months. No significant differences were found in overall or progression-free survival between the two treatment arms.²⁹

Interleukin-2

Cutaneous Melanoma

Dose-related serious toxicities have limited IL-2 studies in melanoma patients, and low-dose IL-2 therapy has produced disappointing clinical response rates.³⁸ When high-dose, 100,000 units/kg, intravenous, recombinant IL-2 was examined in 47 patients with metastatic malignant melanoma, up to 20% achieved objective responses; however, three patients developed myocardial infarction and one patient died during therapy.³⁹ IL- 2-based biochemotherapy (IL-2, IFN-á-2b, cisplatin, dacarbazine, and vinblastine) has shown a response rate of 48%. It appears that this combination is statistically superior to either IL-2 or chemotherapy alone.⁴⁰ Results of ongoing trials may clarify the true value of IL-2 incombination chemotherapy.

IL-12

Cutaneous T-cell Lymphoma

CTCL presents with marked defects in IL-12 production, and progression of CTCL has been associated with profound defects in cell-mediated immunity and cytokine production. A Phase I dose-escalation trial examined the effect of recombinant human IL-12 (rhIL- 12) at a concentration of 50ng/kg, 100ng/kg, or 300ng/ kg, given two times/week subcutaneously for up to 24 weeks in 10 patients with CTCL. A complete clinical response (CR) was defined as complete disappearance of all measurable CTCL lesions for at least 1 month. A partial response (PR) was defined as at least 50% disappearance of all CTCL skin lesions for at least 1 month. Only patients with plaque stage disease (n=2) presented a CR. Two plaque stage patients and one Sézary syndrome patient had a PR. None of the T3 stage patients responded to the rhIL-12 treatment. The authors announced the development of future Phase II/III clinical trials based on the high response rate of plaque stage CTCL patients to rhIL-12.⁴¹

Future clinical trials on immunomodulators will continue to change the approach, management, and follow-up of skin cancer patients. These skin cancer therapies will continue to be based on principles governing the immune system. As our knowledge of the immune system continues to grow, the application of safe and efficacious immunomodulators to treat skin cancer will continue to change the practice of dermatology.

References

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16. Wolf IH, Cerroni L, Kodama K, Kerl H. Treatment of lentigo maligna (melanoma in situ) with the immune response modifier imiquimod. Arch Dermatol 141(4):510-4 (2005 Apr).
17. Berman B, Sullivan T, De Araujo T, Nadji M. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle. Br J Dermatol 149 Suppl 66:59-61 (2003 Nov).
18. Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41(6):1002-7 (1999 Dec).
19. 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 doseresponse trial. J Am Acad Dermatol 44(5):807-13 (2001 May).
20. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two Phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50(5):722-33 (2004 May).
21. Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehiclecontrolled Phase III study in Europe. Br J Dermatol 152(5):939-47 (2005 May).
22. Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two Phase III, randomized, doubleblind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 50(5):714-21 (2004 May).
23. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease. British Association of Dermatologists. Br J Dermatol 141(4):633-41 (1999 Oct).
24. Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML. Imiquimod 5% cream in the treatment of Bowen’s disease. J Am Acad Dermatol 44(3):462-70 (2001 Mar).
25. Zampogna JC, Flowers FP, Roth WI, Hassenein AM. Treatment of primary limited cutaneous Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 11 No. 5 • June 2006 7 extramammary Paget’s disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol 47(4 Suppl):S229-35 (2002 Oct).
26. Berman B, Spencer J, Villa A, Poochareon V, Elgart G. Successful treatment of extramammary Paget’s disease of the scrotum with imiquimod 5% cream. Clin Exp Dermatol 28 Suppl 1:36-8 (2003 Nov).
27. Todd RW, Etherington IJ, Luesley DM. The effects of 5% imiquimod cream on high-grade vulval intraepithelial neoplasia. Gynecol Oncol 85(1):67-70 (2002 Apr).
28. Marchitelli C, Secco G, Perrotta M, Lugones L, Pesce R, Testa R. Treatment of bowenoid and basaloid vulvar intraepithelial neoplasia 2/3 with imiquimod 5% cream. J Reprod Med 49(11):876-82 (2004 Nov).
29. Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized Phase III trial of the DC study group of the DeCOG. Ann Oncol 17(4):563-70 (2006 Apr).
30. Di Nicola M, Carlo-Stella C, Mortarini R, et al. Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic melanoma. Clin Cancer Res 10(16):5381-90 (2004 Aug).
31. Lau R, Wang F, Jeffery G, et al. Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma. J Immunother 24(1):66- 78 (2001 Jan-Feb).
32. Schuler-Thurner B, Dieckmann D, Keikavoussi P, et al. Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocytederived dendritic cells. J Immunol 165(6):3492-6 (2000 Sep).
33. Thurner B, Haendle I, Roder C, et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190(11):1669-78 (1999 Dec).
34. Baar J. Clinical applications of dendritic cell cancer vaccines. Oncologist 4(2):140-4 (1999).
35. Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4(3):328-32 (1998 Mar).
36. Escobar A, Lopez M, Serrano A, et al. Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients. Clin Exp Immunol 142(3):555- 68 (2005 Dec).
37. Banchereau J, Palucka AK, Dhodapkar M, et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61(17):6451-8 (2001 Sep).
38. Atkins MB. Interleukin-2: clinical applications. Semin Oncol 29(3 Suppl 7):12-7 (2002 Jun).
39. Parkinson DR, Abrams JS, Wiernik PH, et al. Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol 8(10):1650-6 (1990 Oct).
40. McDermott DF, Mier JW, Lawrence DP, et al. A Phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res 6(6):2201-8 (2000 Jun).
41. Rook AH, Wood GS, Yoo EK, et al. Interleukin- 12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 94(3):902-8 (1999 Aug).
42. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14(1):7-17 (1996 Jan).
43. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/ S9111/C9190. J Clin Oncol 18(12):2444-58 (2000 Jun).
44. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19(9):2370-80 (2001 May).
45. Korman N, Moy R, Ling M, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two Phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 141(4):467-73 (2005 Apr).

Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, FL

ABSTRACT

Imiquimod is the first of a new class of drugs to emerge in the treatment of various dermatologic disorders. As an immune response modifier, it has been shown to have potent antiviral and antitumor properties through the stimulation of innate and cell mediated immune pathways. It is currently approved for the treatment of external genital and perianal warts, but has also been found to be an effective treatment for a host of other virus-associated dermatologic lesions, including common and flat warts, molluscum contagiosum and herpes simplex 2. Oncological lesions showing improvement with the use of imiquimod include basal cell carcinoma, actinic keratosis, squamous cell carcinoma in situ, malignant melanoma, cutaneous T-cell lymphoma, and cutaneous extramammary Paget’s disease. Recent case studies have also found this product to be effective for treating keloids, infantile hemangioma, porokeratosis of Mibelli, leishmaniasis, and tattoo removal. This extensive array of disorders treated successfully with imiquimod warrants further study of this novel and valuable drug.

Key Words:
imiquimod, immune response modifier

As an immune response modifier, imiquimod 5% cream (Aldara™, 3M) indirectly acts to enhance the body’s natural ability to heal through the induction of innate and cell mediated pathways. Stimulation of these immune pathways leads to the synthesis and release of cytokines, most often interferon-α, tumor necrosis factor-α, interferon-γ and interleukin-12. Activity of natural killer cells, macrophages, B lymphocytes, and Langerhans cells is also enhanced significantly.¹ At present, imiquimod is approved as a topical, patient-applied treatment option for external genital and perianal warts produced by human papillomavirus (HPV).² The efficacy of treatment with imiquimod has been shown to effectively clear external genital warts from 50% up to 75.5%, with the higher numbers present in uncircumcised males, as well as in female patients.^3,4 Owing to its broad immunologic properties, imiquimod has also been documented as a safe and effective treatment for several other skin conditions. In 2001, Sauder categorized a range of conditions that was reported to have been successfully treated with imiquimod into virus-associated conditions, oncological conditions, and other conditions.⁵ Since then, the array of skin conditions successfully treated with imiquimod has expanded.

Virus-associated conditions

Human papillomavirus (HPV)

The antiviral activity of imiquimod has been useful for clearing genital warts produced by HPV, but indirectly. It is not specifically targeted against the HPV types (HPV 6 and 11) that result in genital warts. Therefore, patients with nongenital warts caused by other subtypes of HPV are felt to be prime candidates for treatment, and several case reports illustrate imiquimod’s efficacy in these patients. Fifty patients with common warts were treated with imiquimod once daily for 5 consecutive days over a span of 12 weeks; 30% showed complete clearance and 26% showed a reduction in wart size greater than 50%.⁶ Muzio, et al, reported 10 cases of recurrent common warts, with 8/10 patients showing total remission after application of imiquimod under occlusion once daily for 4 weeks, with no recurrences reported at 3-month follow-up.⁷ In a case report, imiquimod applied nightly 3 times/week demonstrated its potential use in recalcitrant facial flat warts, with complete clearing after 3 weeks of therapy.⁸ Successful treatment of HIV-positive patients with common warts was reported with the length of treatment ranging from 4-12 weeks.^6,9 Other successful cases of treating warts in immunosuppressed patients were reported using a combination of imiquimod with CO2 laser therapy and occlusive treatment.¹⁰ In addition to HPV-induced common warts, Stockfleth, et al, reported a case of HPV DNA-positive generalized stucco keratosis, successfully treated with imiquimod, 3 times/week for 5 weeks.¹¹

Molluscum contagiosum virus (MCV)

Imiquimod has been shown to be effective in other non- HPV associated virally-induced conditions as well. Molluscum contagiosum (MC), caused by a large doublestranded DNA virus of the Poxviridae family, has been successfully treated with imiquimod in both children and adults. Barba, et al, treated the MC lesions of 13 children with imiquimod in an open-label safety study for 4 weeks, with full resolution of baseline target lesions in 12/13 children and no evidence of systemic toxicity. The one patient who did not complete the study experienced severe erythema, local superficial forehead erosion, and hypopigmentation that slowly resolved.¹² Liota, et al, also included children in their patient population, as the molluscum contagiosum virus (MCV) is most commonly seen in young children, sexually active adults, and in some immunosuppressed patient populations. In a 16-week trial using imiquimod 3 times/week, 14/19 immunocompetent adults, 4/4 HIV-positive adults, and 6/13 children had resolution of their MC lesions, with more local inflammatory and pruritic reactions occurring among the children. In areas expected to have greater penetration of a topical agent (e.g., the axillae) clearing was more consistently observed.¹³ An open-label study also examined imiquimod’s effect on patients with common warts or MC, and showed total clearance of MC lesions in 8/15 (53%) patients or a >50% reduction in molluscum size in 4/15 (27%) patients. The mean duration of treatment was 9.8 months (range 2-24), and there were no differences found with regard to gender or HIV status.⁶ As MCV does not develop latency, but evades the immune system in other ways, the clearance of MC lesions tends to reflect longterm cure.¹³ Several case studies have also illustrated the efficacy of imiquimod for treating MC lesions of immunocompromised populations. Buckley, et al, described the case of an HIV-1 positive woman with extensive disfiguring MC lesions who had failed cryotherapy, 0.5% podofilox, and 0.5% tretinoin.¹⁴ Brown, et al, described a similar case of MC, which had also failed conventional therapies with cryotherapy and trichloroacetic acid crystalline solution.¹⁵ In both cases, topical imiquimod resulted in full clearance of the treated lesions with no systemic adverse effects, but stable postinflammatory hyperpigmentation developed.

Herpes simplex virus 2 (HSV-2)

Topical imiquimod offers an alternative for treating herpes simplex virus (HSV) infections, particularly in the setting of emerging resistance. A 34-year old HIV-positive man who developed a HSV-2 infection of the penis resistant to acyclovir, valacyclovir hydrochloride, and famiciclovir was successfully treated with imiquimod applied 3 times/week for 1 week, with no recurrences after 1-month of follow-up. This report may support the use of topical imiquimod as an effective treatment for HSV infections, particularly in the setting of acyclovir resistance or unresponsiveness.¹⁶

Oncological and oncologically related conditions

Basal cell carcinoma (BCC)

A series of clinical trials and case reports document the effectiveness of imiquimod for treating superficial or nodular basal cell carcinomas (BCCs) on low-risk sites.^17-22 Efficacy seems to be dose-related. For superficial basal cell carcinoma, cure rates vary from 69.7% up to 100%.^19,20 Nodular BCC cure rates are just below 80%, and do not reach the level of complete clearance expected of a first line monotherapy.^22-24 Currently, there is no consensus as to the most effective treatment regimen using imiquimod, and complete response has been reported in as little as 6 weeks up to 18 weeks.^{20, 26} Optimal dosing to minimize cutaneous side-effects and maximize efficacy has not been determined; studies suggest that treatment should be dosed 3-5 times/week. Rest periods have also been recommended.²⁰ Complete (100%) compliance with dosing did not appear necessary to achieve a complete efficacy response.²⁰ Though statistically significant correlation has been established between the most intense erosion reaction assessed by the investigator and a complete response, twice daily application was reported to produce unacceptable skin reactions. Daily application seems the most suitable for use in clinical practice on the basis of efficacy, tolerability, potential cost of treatment, and likelihood of compliance for a lengthy period of treatment.^{20, 24} The cosmetic outcome has been excellent.^{20, 22} Special cases of BCCs treated with imiquimod include a large (5×6 cm) superficial BCC,25 a patient with Basal Cell Nevus Syndrome and multiple BCCs,^{26, 27} and a report of two siblings with xeroderma pigmentosum, in whom topical imiquimod reduced the rate of new tumor formation, permitting dermatologists to “keep up” with the surgical treatment of new lesions.²⁸ Further clinical trials are required to confirm efficacy in larger BCCs and BCCs with aggressive growth patterns.

Actinic keratosis (AK)

Imiquimod was documented in a few studies as a useful treatment option for AK. A double-blind pilot study²⁹ examined 41 AK patients applying imiquimod or a vehicle cream in different dosing groups to three target AKs for up to 16 weeks, with clinical resolution of all target lesions. In another randomized, double-blind study,³⁰ 36 patients with AK lesions applied imiquimod or a vehicle cream 3 times/week for 12 weeks or until resolution, which occurred in >80% of patients. Six case reports of men with AK were described, where imiquimod was applied 3 times/week for 6-8 weeks. In the event of a local skin reaction, treatment was modified to 2 times/week. All of the AK lesions successfully cleared and there were no reports of recurrence (ranging from 2-12 months post-treatment).³¹ In a small trial involving 22 patients, their AKs were treated with imiquimod initially at 3 times/week for 8 weeks or until there was total clearance of the lesions. ³² By the end of the study, a significant reduction in the average number of lesions per patient was observed. Salache, et al, used imiquimod to treat 25 AK patients in specific dosing cycles, alternating treatment weeks with weeks of rest and continuing such treatment until complete clearance was achieved.³³ This study, along with others requiring rest periods for local adverse reactions, underscores the need to determine appropriate dosing regimens for patients with AK and other cutaneous lesions.

Squamous cell carcinoma in situ (Bowen’s disease)

Treatment modalities for squamous cell carcinoma in situ (Bowen’s disease) often have significant risk of scarring, deformity, and poor cosmetic appearance. Surgery on common areas for Bowen’s disease (lower limbs, head, neck) may be anatomically difficult. With this in mind, Mackenzie-Wood, et al, treated 16 patients in a phase II, open-label study, where imiquimod was applied to biopsyproven plaques of Bowen’s disease once daily for 16 weeks. Six-week post-treatment biopsies revealed no residual tumor in 14/15 patients (the 16th patient was unavailable for biopsy), although 6 patients found it necessary to stop treatment early due to intense local skin reactions during the study.34 Several case reports have illustrated the efficacy of imiquimod in treating Bowen’s disease of the penis.^{35, 36} A 65-year old circumcised male applied imiquimod nightly until intense local erythema and erosions developed. A rest period was given before treatment was resumed. Follow-up at 18-months post-treatment revealed no residual or recurring tumor and no evidence of scarring, deformity, or loss of function.³⁶ Imiquimod has also been shown to be effective in combination with 5% flurouracil (5-FU) therapy in immunosuppressed populations. A recent case study reported an HIV-positive male with perianal Bowen’s disease treated with 5-FU and imiquimod in the same time frame. By 16 weeks, clinical and symptomatic improvement occurred without persisting or recurring lesions.³⁷ Smith, et al, also presented five cases of renal transplant patients treated with imiquimod and 5-FU for Bowen’s disease in multiple areas following their transplants. Topical application of both imiquimod and 5-FU was instigated 3 times/week until complete resolution of the lesions was achieved in all of the patients, with no residual lesion at 3-15 month post-treatment follow-up visits.³⁸

Bowenoid papulosis

Bowenoid papulosis is histologically seen as a carcinoma in situ, despite the benign course of the condition. In 2001, a case report described the effect of imiquimod applied on alternating days for 10 days, or until the skin became visibly irritated and a new dosing schedule was assigned (application once daily for another 10 days, washed off after 2 hours). Complete clinical resolution was noted within 8 weeks and histology revealed no persisting or recurring disease. The patient remained clinically clear after more than 18 months off treatment.³⁹

Vulvar intraepithelial neoplasia (VIN)

A large percentage of vulvar intraepithelial neoplasias (VIN3) have been shown to harbor human papillomavirus (HPV). Imiquimod, an effective treatment for external and perianal genital warts caused by HPV, is thought to be a potentially beneficial treatment for patients with VIN3 of viral (HPV) etiology. A prospective study of 15 patients with high-grade VIN3 examined the effects of imiquimod, self-applied 3 times/week to vulvar lesions for 16 weeks. Only 13/15 patients were able to complete the study, and of those, only 4 showed visible clinical improvement in the state of their condition. The rest of the patients did not improve using imiquimod, although local side-effects such as soreness and burning limited the frequency of cream application, and therefore may have contributed to the patients’ lack of improvement.40 Four cases of imiquimodtreated VIN3 were also reported, with a regimen of selfapplied imiquimod to vulvar lesions 3 times/week until all lesions cleared, for up to 16 weeks. Three of the patients had recurrence of their lesions, with one of the recurrences occurring (and treated with further imiquimod use) during the trial. Other recurrences developed 1 year posttreatment, inside and outside the original field of treatment. These patients were only instructed to use imiquimod during the time of the study, and it is postulated that extended treatment and long-term follow-up may prevent future recurrences.⁴¹

Melanoma

Imiquimod has also been useful for treating melanoma. In a case report, a patient reluctant to have a large lentigo maligna of the scalp excised underwent a complete clinical and histological cure after application of imiquimod for 7 months to an initial test area inside the lesion, then to the entire lesion. No clinical recurrence was reported at 9-month follow-up. The recommended treatment for lentigo maligna is conventional surgery, using a 5-10mm margin. Imiquimod may be a novel treatment option worthy of consideration for carefully selected patients in whom more traditional therapy is not considered feasible.⁴² Likewise, a 50-year-old female suffering from disseminated cutaneous metastatic melanoma lesions was treated with imiquimod 3 times/day with continuance of dacarbazine. Lesions were too initially widespread to be treated with excision or radiotherapy, and failed to improve after a cycle of dacarbazine alone. After 12 weeks of treatment with imiquimod, metastases were no longer detected.⁴³

Cutaneous T-cell lymphoma (CTCL)

A case of cutaneous T-cell lymphoma (CTCL) recently reported complete clearance of clinical and subclinical disease after 4 months of therapy with imiquimod. There was no recurrence at the treatment site at 10-month followup. The authors have initiated a double blind, placebocontrolled trial to better evaluate the efficacy of imiquimod in the treatment of CTCL.⁴⁴

Cutaneous extramammary Paget’s disease (EMPD)

Extramammary Paget’s disease is an infrequent epidermal malignancy, occurring most commonly in the anogenital and vulvar regions. Berman, et al, treated a case of cutaneous scrotal EMPD with once-daily, self-applied imiquimod over a period of 6 weeks. Though local erythema developed in the treatment area, no systemic symptoms were noted and clinical resolution occurred by week-4 of treatment, with no remaining pathology at 6-month followup. ⁴⁵ Two other cases of perineal and genital EMPD have also been recently reported, with clinical cure occurring after applying imiquimod on alternating days of the week for 7.5 to 12 weeks. Although it was concluded that this treatment modality was a much less invasive therapeutic option, both cases were associated with systemic symptoms that included flu-like symptoms (malaise, fatigue, lowgrade fever), as well as nausea and vomiting.⁴⁶

Actinic cheilitis

A retrospective review of 15 patients receiving topical imiquimod as a single agent 3 times/week for the treatment of actinic cheilitis was recently published. Clearance of the treated area was reported in six patients after 4 weeks of treatment, and in the remaining nine patients after week 6. Since it is possible for this condition to progress to invasive squamous cell carcinoma, it is mentioned in this category of oncologically-related conditions.⁴⁷

Other conditions

Keloids

Berman and Kaufman recently examined the effects of postoperative, topical application of imiquimod to 13 keloids excised from 12 patients. It was applied nightly for 8 weeks, with no recurrence of keloidal growth among the 11 keloids (10 patients completed the study) evaluated at 24 weeks, a rate that was lower than previously reported recurrence rates. The two remaining patients, though lost to follow-up, had completed the 8-week treatment phase and had no keloid recurrence at the time they left the study. Mild local reactions occurred, but were resolved with temporary discontinuation, and no systemic effects were noted.⁴⁸

Infantile hemangioma

Imiquimod, used to treat two cases of infantile hemangioma of postnatal onset showed complete resolution of these scalp lesions in the proliferative state within 3-5 months. Though the development of erythema and crusting necessitated resting periods, both cases showed virtually complete clinical regression without scarring and neurologic abnormalities. The authors have launched a larger clinical study with pathologic correlation and a mechanism-oriented investigation.⁴⁹

Porokeratosis of Mibelli

Agarwal and Berth-Jones recently reported a patient with a clinical and histological diagnosis of porokeratosis of Mibelli, successfully treated with imiquimod once-daily for 5 days/week. The initial 3-month treatment showed no response. Subsequently, the same dosage and frequency of imiquimod was used, but under occlusion with an adhesive polythene dressing (Tegaderm®, 3M). The lesion cleared after 5 weeks of treatment, without recurrence at 1-year follow-up. The authors suggested that in the case of porokeratosis of Mibelli, imiquimod application may need to be followed by occlusion due to its inability to penetrate the lesion sufficiently. Although it is possible that occlusion alone would have proven to be therapeutic, the authors believe it is unlikely.⁵⁰

Leishmaniasis

An open-label, prospective study of combined meglumine antimonate plus imiquimod therapy was conducted in 12 patients with cutaneous leishmaniasis who had previously not responded to a complete course of meglumine antimonate monotherapy. All of the patients responded well to this combination therapy, and 90% were cured at the 6- month follow-up period. Although imiquimod as a solo agent has previously failed to be effective in the treatment of cutaneous leishmaniasis, this study shows that there may be a synergistic effect between imiquimod and meglumine antimonate responsible for the cure of these cases of cutaneous leishmaniasis.⁵¹

Tattoo removal

Imiquimod was used for experimental nonsurgical tattoo removal in a guinea pig model using topical imiquimod. Application began 6 hours after tattooing, and treatments were applied every 6 hours for up to 7 days, with no visible tattoo showing at day 28. This is consistent with greatly diminished or no dye evident on histopathology, but is associated with fibrosis and the loss of dermal appendages. This study addressed the treatment of acute-phase tattoos. The authors suggested that early clinical intervention with imiquimod may eventually play a role in the nonsurgical management of tattoo allergy, especially if laser therapy is not an option.⁵²

Conclusion

Imiquimod 5% cream is currently approved for use in genital and perianal warts. However, it may also be an effective treatment for a variety of other entities. As a topical agent, application of imiquimod is convenient because it is patient-applied and reduces the necessity for surgical excision. It is important to note that recent literature regarding imiquimod’s newer uses consists mostly of case studies. Additional assessment in controlled studies is warranted for each of these conditions. Such studies should take place over longer periods of time, during and after the treatment phase and attention should be paid to the dosing frequency. Furthermore, because imiquimod induces production of interferons, and enhances Th1 cell-mediated immune responses, it can be potentially useful in the treatment of conditions that respond to interferon therapy, such as Kaposi’s sarcoma and chronic granulomatous disease.⁵³ Other potential uses may stem from imiquimod’s ability to also inhibit Th2 responses, and therefore may be useful in treating such entities as atopic dermatitis.⁵

References

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