Abstract: Cervical intraepithelial neoplasia (CIN) is a common disease among women of reproductive age. High-grade CIN lesions (CIN 2–3) are precancerous and can progress to cervical cancer. The most important risk factor for the development of CIN and progression to cervical cancer is persistent high-risk human papillomavirus (HPV) infection. The preferred treatment in most countries is surgical excision using conization. There is high need for a medical treatment alternative to surgical therapy for CIN 2–3 largely because of the risk of preterm birth and other long-term sequelae of cervical conization in future pregnancies. No medical therapy has been established in clinical practice for patients with CIN 2–3.
In 2008, a study reported on the efficacy of imiquimod, a topical immune response modulator, against HPV-related vulvar intraepithelial neoplasia. Earlier this year, a randomized controlled trial found that combined use of imiquimod and conization did not improve CIN 2–3 recurrence rates compared with use of conization alone. However, the study had a number of design flaws. A major problem was the application of imiquimod only 5 times before surgery, an uncommon and short treatment regimen.
The aim of the present randomized, double-blind, placebo-controlled phase 2 trial was to estimate the therapeutic efficacy of vaginal, self-applied imiquimod in women with high-risk HPV-positive CIN 2–3. Study subjects were 59 patients with untreated, histologically proven, high-risk, HPV-positive, and newly diagnosed CIN 2–3. Eligible women were randomized to receive either treatment with self-applied vaginal suppositories containing imiquimod or placebo for 16 weeks. The primary study outcome was efficacy, defined as histologic regression to CIN 1 or less following treatment. Secondary outcomes included complete histologic remission, HPV clearance, and treatment tolerability. A sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2–3 regression (imiquimod vs. placebo), assuming a 2-sided 5% significance level and a power of 80%. All patients tested positive for high-risk HPV at baseline.
After 16 weeks of treatment, histologic regression to CIN 1 or less was achieved in 73% in the imiquimod group compared with 39% in the placebo group (P = 0.009). There was a higher complete histologic remission in the imiquimod group (47%) than in the placebo group (14%) (P = 0.008). Human papillomavirus clearance rates after treatment were 60% in the imiquimod group and 14% in the placebo group (P < 0.001). Complete remission rates among patients with HPV-16 infection were 47% in the imiquimod group and 0% in the placebo group (P = 0.003). Three of the 59 patients (5%), all within the placebo group, were found to have microinvasive cervical cancer after treatment. Topical imiquimod had no high-grade adverse effects; treatment was well tolerated.
These findings suggest that vaginal imiquimod therapy is an efficacious, feasible, and well-tolerated medical treatment for patients with CIN 2–3.