Comparison of Treatment of Cervical Intraepithelial Lesions With Imiquimod or LLETZ

Purpose: There are limited data on the success of conservative treatment of high-grade cervical squamous intraepithelial lesions (HSIL) with imiquimod directly compared to standard of treatment with LLETZ. LLETZ as standard treatment is possibly associated with premature labour, higher subfertility rate and a higher rate of spontaneous abortion. Since premature delivery is one of the most important causes of perinatal morbidity and mortality, alternative conservative methods for SIL treatment are constantly being evaluated. The immunomodulator imiquimod is one of the main target compounds for treating HSIL. Primary objective: to establish the efficacy of treatment with imiquimod (experimental arm) and compare it to the standard treatment with LLETZ (control arm). Secondary objective: * incidence and severity of the side effects in both groups; * need for treatment with LLETZ two years after primary treatment with imiquimod in the experimental arm or re-treatment with LLETZ two years after primary treatment with LLETZ in the control arm; * modulatory effect of imiquimod on immunoregulatory molecules. Study design: Single-centre randomized controlled intervention trial. Study population: 104 women with HSIL (52 in each arm). Intervention: \- randomization in two arms: 1. Experimental arm (imiquimod): treatment for 16 weeks with 5% imiquimod. 2. Control arm (LLETZ). Successful treatment in the experimental arm is defined as absence of histological HSIL in diagnostic biopsies at 20-week follow-up (4 weeks after treatment completion) and in the control arm successful treatment is defined as absence of cytological HSIL in cytology 6 months after LLETZ (same as in our national guidelines).

Sex

Female

Minimum age

18 Years

Maximum age

40 Years

Inclusion Criteria:

* newly diagnosed and previously untreated HSIL in women aged 18 to 35 years or up to 40 years in case of nulliparity;
* satisfactory colposcopy (i.e., fully visible lesion and transformation zone);
* negative pregnancy test;
* safe contraception;
* signed, informed consent.

Exclusion Criteria:

* previously diagnosed HSIL or AIS;
* previous LLETZ or classical conisation;
* concomitant vulvar or vaginal lesion or neoplasia;
* other malignancies;
* insufficient colposcopy;
* pregnancy or lactation;
* known hypersensitivity to imiquimod;
* any known contraindications to immunotherapy;
* known HIV or acute or chronic hepatitis;
* immune deficiency;
* participation in any other ongoing clinical trial.

• BACKGROUNDGrimm C, Polterauer S, Natter C, Rahhal J, Hefler L, Tempfer CB, Heinze G, Stary G, Reinthaller A, Speiser P. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol. 2012 Jul;120(1):152-9. doi: 10.1097/AOG.0b013e31825bc6e8. PMID 22914404
• BACKGROUNDde Witte CJ, van de Sande AJ, van Beekhuizen HJ, Koeneman MM, Kruse AJ, Gerestein CG. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review. Gynecol Oncol. 2015 Nov;139(2):377-84. doi: 10.1016/j.ygyno.2015.08.018. Epub 2015 Aug 31. PMID 26335596
• BACKGROUNDKoeneman MM, Kruse AJ, Kooreman LFS, Zur Hausen A, Hopman AHN, Sep SJS, Van Gorp T, Slangen BFM, van Beekhuizen HJ, van de Sande M, Gerestein CG, Nijman HW, Kruitwagen RFPM. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 2016 Feb 20;16:132. doi: 10.1186/s12885-016-2187-3. PMID 26897518
• BACKGROUNDJancar N, Mihevc Ponikvar B, Tomsic S. Cold-knife conisation and large loop excision of transformation zone significantly increase the risk for spontaneous preterm birth: a population-based cohort study. Eur J Obstet Gynecol Reprod Biol. 2016 Aug;203:245-9. doi: 10.1016/j.ejogrb.2016.06.005. Epub 2016 Jun 20. PMID 27359080
• DERIVEDCokan A, da Silva NCH, Kavalar R, But I, Pakiz M, Andrade de Oliveira S, Dos Santos Gomes FO, da Silva RS, Peixoto CA, Lucena-Silva N. Modulation of sHLA-G, PD-1, and PD-L1 Expression in Cervical Lesions Following Imiquimod Treatment and Its Association with Treatment Success. Cancers (Basel). 2024 Mar 25;16(7):1272. doi: 10.3390/cancers16071272. PMID 38610950