Topical Treatment Found Effective for Vulvar Intraepithelial Neoplasia

By Todd Neale
ROTTERDAM, April 4 -- For vulvar intraepithelial neoplasia, imiquimod (Aldara) 5% cream reduced lesion size and cleared human papillomavirus better than placebo, researchers here found.Lesion size was decreased by more than 25% in 21 of 26 patients who used imiquimod compared with none in the placebo group (P<0.001), Theo Helmerhorst, M.D., Ph.D., of Erasmus University Medical Center here, and colleagues reported in the April 3 issue of the New England Journal of Medicine.The lesions had disappeared in significantly (P<0.001) more of the patients using the topical treatment (35%) than in those using placebo (0%). All of these patients remained disease-free at one year.
"We consider imiquimod the first-choice treatment for vulvar intraepithelial neoplasia," the Dutch researchers concluded.
Although surgery has been the treatment of choice for the disease, it has limitations, they said.
From 24% to 68% of lesions have positive surgical margins and surgery does not eliminate HPV, which causes most vulvar intraepithelial neoplasia.
Surgery can also disfigure the vulva and cause psychosocial distress, according to the researchers.
As an alternative, imiquimod, a topical immune response modifier, has been shown to be effective in small, uncontrolled studies, they said.
Imiquimod binds to toll-like receptor 7, a cell-surface receptor on the immature plasmacytoid dendritic cell, starting a cascade that increases immune response.
To test its effectiveness in a double-blind, randomized, placebo-controlled study, the Dutch team enrolled 52 women older than 18 who had grade 2 or 3 vulvar intraepithelial neoplasia. All were seen at the Academic Medical Center of the University of Amsterdam or the Erasmus University Medical Center from April 2001 through July 2003.
Mean time from diagnosis of the disease was 5.4 years (range one month to 20 years).
Twenty-six participants were randomized to 250 mg of imiquimod 5% and 26 to placebo cream twice weekly for 16 weeks. All were advised to use sulfur precipitate 5% in zinc oxide ointment the day after application to avoid superinfection.
The patients were monitored every four weeks and endpoints were evaluated at 20 weeks after starting treatment. Long-term follow-up was conducted at seven months and one year.
During follow-up, one patient in the imiquimod group dropped out because her lesions had disappeared and one placebo patient withdrew because of a lack of response.
Regression to a lower grade of vulvar intraepithelial neoplasia was found in 18 imiquimod patients (69%) and one using placebo (4%) (P<0.001).
One patient using imiquimod worsened from grade 2 to grade 3.
Invasion to a depth of less than 1 millimeter occurred in one imiquimod patient at seven months and two placebo patients, one at 20 weeks and one at 12 months.
The researchers found a strong association between regression of the disease and clearance of HPV (P<0.001). Of 14 lesions that regressed to grade 1 or disease-free, 13 were cleared of the virus with imiquimod and one was not infected with the virus at baseline.
During treatment, patients in the imiquimod group had significantly more vulvar pain or pruritus (P<0.001), apathy (P=0.03), mild-to-moderate erythema (P<0.001), severe erythema (P=0.02), mild-to-moderate erosion (P=0.001), and edema (P<0.001).
Half of the placebo patients (13) had no side effects compared with one of the imiquimod patients (P<0.001).
However, imiquimod significantly reduced pruritus and pain at 20 weeks (P=0.008 and P=0.004, respectively) and 12 months (P=0.04 and P=0.02, respectively) compared with placebo.
The researchers concluded, "As a convenient, self-administered treatment, imiquimod is well tolerated, is less invasive than surgery, relieves itching and pain, and does not influence health-related quality of life, body image, or sexuality."
The study was supported by the Erasmus University Medical Center and the Academic Medical Center. 3M Pharmaceuticals, maker of imiquimod, provided the study medication and performed the randomization.

Primary source: New England Journal of MedicineSource reference:van Seters M, et al "Treatment of vulvar intraepithelial neoplasia with topical imiquimod" N Engl J Med 2008; 358: 1465-1473.