Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer and is caused by cervical human papillomavirus (HPV) infection [
]. The natural history of individual CIN lesions is unpredictable. Approximately 30 % of high-grade CIN progresses to cervical cancer [
]. On the contrary, recent evidence suggests that spontaneous regression occurs in approximately 20–40 % of high-grade lesions [
]. Current histopathological assessment is unable to differentiate between lesions that will progress to cervical cancer and those that will regress spontaneously. Therefore, all high-grade CIN lesions are currently treated by surgical excision, consisting of large loop excision of the transformation zone (LLETZ). This treatment is associated with potential complications. Short term complications include pain, vaginal discharge and bleeding. The most serious late complication is premature birth in subsequent pregnancy, probably due to cervical insufficiency [
]. Evidence shows a two fold increase in premature birth between 32/34 and 37 weeks in patients who were treated with LLETZ. Furthermore, cervical surgery for CIN may be associated with subfertility. A recent case–control study in 152 patients who underwent cervical surgery showed a twofold increase in prolonged time to conception (16.4 % vs 8.6 %) for patients who underwent LLETZ [
]. Since cervical dysplasia is most common in women of childbearing age, these potential complications are of special interest to the patient population and surgical intervention should be avoided if possible. Therefore, an effective non-invasive treatment modality is needed. A potential agent in non-invasive therapy is imiquimod cream. Imiquimod is an immunomodulator with antiviral and anti-tumour effects. It is a toll-like receptor 7 agonist and induces up regulation of interferon and activation of dendritic cells [
]. It is currently used in treatment of basal cell carcinoma, actinic keratosis and external genital warts in adults. As an off-label drug, it has also been proven effective in the treatment of HPV related vulvar intraepithelial neoplasia (VIN) [
]. The use of imiquimod in CIN has been studied by several authors [
]. Only one randomized controlled trial was conducted, evaluating the efficacy of imiquimod treatment in high-grade CIN [
]. Grimm et al. included 59 patients, who were randomized for treatment with imiquimod or placebo during 16 weeks. The study results are promising: both histologic regression and complete remission of high-grade CIN was significantly more frequent in patients treated with imiquimod, compared to the control arm (73 % vs 39 % and 47 % vs 14 % respectively). However, side-effects seem common and long-term outcomes are unknown.
Ideally, the response to imiquimod treatment of an individual patient would be predictable. Previous studies have shown that the natural behaviour of CIN lesions can be partially predicted by biomarker models, consisting of markers that reflect host, viral and cellular factors [
]. This study aims to develop a similar biomarker prediction model for the individual response to imiquimod treatment, in order to enable individualized treatment of CIN lesions.
This study aims to confirm the short and long term efficacy of imiquimod 5 % cream in the treatment of high-grade CIN, as well as to evaluate clinical applicability by assessment of side-effects and quality of life during and after treatment. Additionally, it aims to develop a biomarker prediction model for clinical response to imiquimod treatment of high-grade CIN. For this purpose, we designed a randomized controlled trial with two arms, in which imiquimod treatment is compared to standard treatment by LLETZ. The trial was designed according to the CONSORT guidelines.