More Medical Therapy for a Traditionally Approached Surgical Disease: VIN
More Medical Therapy for a Traditionally Approached Surgical Disease: VIN
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Topical application of the immune stimulant, 5% imiquimod (Aldara™, 3M) effectively reduces high-grade VIN in 81% of treated women in this double-blind, placebo-controlled clinical study.
Source: Treatment of Vulvar Intraepithelial Neoplasia with Topical Imiquimod. Van Seters M, et al. N Engl J Med. 2008;358:1465-1473.
Alternatives to surgical management of vulvar intraepithelial neoplasia (VIN) are needed given the high recurrence risk and need for frequent excisional procedures. Imiquimod, a known interferon-mediated immune-response modifier was investigated in this double-blind, placebo-controlled clinical study. Women aged 18 and older with histological evidence of VIN were enrolled in this two institutional trial where treatment consisted of lesional ointment application twice weekly for 16 weeks. The primary efficacy outcome variable was a reduction in one-month post-treatment lesion size as quantified by computer-assisted image analysis. Secondary outcomes included histologic downgrading, HPV viral clearance, recurrence at 1-year post therapy, toxicity, quality of life and analysis of local immune cells. Fifty-two women (26 in each group) were enrolled. Lesion size reduced more than 25% at 20 weeks in 81% of treated patients; none regressed in the control group. This was accompanied by a similar reduction in histologic grade. At enrollment, 50 of 52 patients were HPV positive; clearance was observed in 15 of 26 treated women compared to 2 or 26 in the placebo group. Immune cells in the dermis were reduced and accompanied by an increase in epidermal immune cells associated with imiquimod. Pruritis and pain were significantly reduced with the active ointment, both at the post-treatment and 1-year evaluations. Treatment-related toxicity was common and more severe in the imiquimod group, but excluding a significantly increased rate of severe erythema (6 patients), the reactions were mild. Invasive disease was observed in 3 patients; all were microinvasive (<1mm); 2 were in the control group, 1 in the treatment group. Complete lesion regression was observed in 9 patients at 20 weeks (all in the imiquimod group) and were also disease-free at 1 year. Quality of life assessment scores were unaffected in either group. This report represents the first to formally assess the efficacy of 5% imiquimod topical therapy for the treatment of women with histologically confirmed VIN.
Commentary
Vulvar intraepithelial neoplasia is a prevalent dermatosis caused, to a large degree, from human papilloma virus (HPV) infection. Host immune function alterations ascribed to this pathogen, most notable for precancerous and cancerous changes in the uterine cervix epithelium, has been the target of prevention and treatment strategies in hopes of obviating the need for surgical intervention. Traditional management of vulvar dysplasia has been biopsy to establish the diagnosis and to rule out invasive disease followed local excision or destruction. For isolated lesions the treatment may be minimal and associated with complete response without significant morbidity. However, most, as evidenced in this trial with just 28% of the participants having reported no prior therapy for VIN, undergo multiple operations/procedures for recurrence or persistent disease. This exacerbates the risk for genital scarring, disfiguration and psychosexual dysfunction. Clearly, given the etiology of this lesion, alternatives are needed.
Multiple non-surgical approaches have been suggested or investigated for intraepithelial neoplasia including, interferon -a and -y , COX-2 inhibitors, dimethyl sulfoxide (DMSO), retinoids, and imiquimod. This latter agent is an immune-response modifier, which has indirect and direct mechanistic functions, including local induction of interferon production, cell-mediated immune response following toll-like receptor binding and pro-apoptotic activity. The efficacy of these strategies has been variable and predominantly studied in uncontrolled small case series. In this relatively modest randomized, double-blinded, placebo-controlled study, the efficacy of imiquimod is clear. The strengths of this report include its design and standardization of lesion size quantification. What we expected to happen, happened, and did so in a rational way — exploiting the immune response. It was of interest that patients identified as major responders (75% or more reduction in lesion size) were characterized as early as 4 weeks into therapy with a significant increase in CD1a+ dendritic cells, CD8+ T-cells and CD94+ NK cells in the epidermis. This may afford modification of a medical treatment approach with early intervention in those patients not demonstrating immune modification. Adjuvants could be employed at this point. Invasive disease is a major concern for non-excisional approaches of VIN and it was not averted in this study. However, the rate of underlying cancer or progression to cancer following surgery was similar to historical reports.
The impact of this report will undoubtedly lead to some modification of clinical practice, and it is welcomed. Observation of treatment effects, though, must be vigilantly carried out to avoid unrecognized progressive invasive disease.
Suggesting Reading
- Schön MP, Schön M. Imiquimod: mode of action. Br J Dermatol. (2007)157, Suppl 2:8-13.
- Diaz-Arrastia C, et al. Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5%. Clin Cancer Res. (2001)7:3031-3033.
- Todd RW, et al. Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia. Gynecol Oncol. (2004) 92:167-174.
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