Imiquimod in patients with cervical intraepithelial neoplasia

Imiquimod in patients with cervical intraepithelial neoplasia | Image Credit: © pikselstock - © pikselstock - stock.adobe.com.

According to a recent study published in Obstetrics & Gynecology, imiquimod is effective for treating cervical intraepithelial neoplasia (CIN).

Imiquimod, an agent with antiviral and antitumor properties, encourages an immune response through the production of cytokines such as interferon-α, interleukin-6, and interleukin-8. The FDA has approved imiquimod for use against actinic keratosis, external genital warts, and basal cell carcinoma. Off-label uses of imiquimod include treating neoplasms.

Human papillomavirus (HPV) infection is associated with CIN and vaginal intraepithelial neoplasia (VAIN), both of which are precancerous conditions. CIN is most often treated by removing the lesion through surgery, but this treatment leads to a greater risk of preterm birth for future pregnancies.

Treatments for VAIN include carbon dioxide laser, surgical treatment, radiation therapy, and 5-fluorouracil, but these methods are associated with high rates of recurrence. Imiquimod, which has been indicated as a potentially effective treatment against CIN, may also be used to treat VAIN. However, there is little data on adverse events related to vaginal use of imiquimod.

To determine the efficacy and adverse events of imiquimod as treatment against CIN and VAIN, investigators conducted a systematic review and meta-analysis. The primary outcomes measured were, “histologic regression of the disease” and treatment discontinuation because of adverse events.

Secondary outcomes included abdominal pain, abnormal vaginal discharge or genital bleeding, arthralgia or myalgia, fever, vaginal ulceration, vulvovaginal pain, HPV clearance, and the presence of adverse events for more than 2 weeks following discontinuation of treatment.

Randomized controlled trials (RCTs) and nonrandomized studies evaluating imiquimod for treating CIN or VAIN were included in the search, with nonrandomized studies included only for assessing adverse events. Studies from database inception to November 23, 2022, were eligible for analysis.

Databases evaluated included PubMed, ISRCTN registry, Cochrane Central Register of Controlled Trials ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform.

Studies were screened by 2 independent reviewers, with a third reviewer consulted during disagreements. Data extracted included imiquimod characteristics, patient characteristics, and outcomes of interest.

Two reviewers independently assessed the risk of bias, evaluating most studies using version 2 of the Cochrane risk-of-bias tool, RoB 2, and ROBINS-I, a tool for assessing risk of bias in nonrandomized studies.

There were 8 studies included in the final analysis, of which 2 were RCTs for CIN and 1 a non-RCT for CIN. Seven of the studies only included patients with CIN 2–3 or VAIN 2–3. The final study included patients with CIN 1 and was excluded from efficacy evaluation.

In 5 studies, 5% imiquimod cream was used for treatment, while vaginal suppository was used for the other 3. Of the studies using 5% imiquimod cream, 2 saw treatment applied by physicians, while the cream was self-applied in the remaining studies.

During bias assessment of the 4 RCTs included for efficacy analysis, 2 had low risk of bias, 1 had moderate risk of bias, and 1 had high risk of bias. Of the 7 RCTs included for safety analysis, 2 had low risk of bias, 1 had moderate risk of bias, and 4 had high risk of bias.

The primary efficacy outcome had a pooled odds ratio (OR) of 4.05, with low heterogeneity between studies. In the imiquimod group, the pooled response rate was 0.61. Safety outcomes had a pooled proportion of 0.07, with moderate heterogeneity between studies. HPV clearance had a pooled OR of 9.50, and the imiquimod group had a pooled response rate of 0.51.

Overall, these results indicated improved efficacy from imiquimod compared to placebo or no intervention when evaluating HPV clearance. However, when separating CIN and VAIN, CINN had a pooled OR of 4.27 for regression, while measurements were uncertain for VAIN because of a small sample size. Investigators recommended further studies on imiquimod administration.

Reference

Inayama Y, Takamatsu S, Hamanishi J, et al. Imiquimod for cervical and vaginal intraepithelial neoplasia: asystematic review and meta-analysis. Obstet Gynecol. 2023. doi:10.1097/AOG.0000000000005256