Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix: A Randomized Controlled Trial

Bruno O Fonseca, Júlio C Possati-Resende, Mila P Salcedo, Kathleen M Schmeler, Guilherme S Accorsi, José H T G Fregnani, Marcio Antoniazzi, Naitielle P Pantano, Iara V V Santana, Graziela M Matsushita, Ricardo Dos Reis, Bruno O Fonseca, Júlio C Possati-Resende, Mila P Salcedo, Kathleen M Schmeler, Guilherme S Accorsi, José H T G Fregnani, Marcio Antoniazzi, Naitielle P Pantano, Iara V V Santana, Graziela M Matsushita, Ricardo Dos Reis

Abstract

Objective: To evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream.

Methods: In this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2-3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses.

Results: Ninety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain.

Conclusion: Weekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL.

Clinical trial registration: ClinicalTrials.gov, NCT03233412.

Conflict of interest statement

Financial Disclosure Júlio C. Possati-Resende disclosed they received money from Becton, Dickinson, and Company. The other authors did not report any potential conflicts of interest.

Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.

Figures

Fig. 1.. CONSORT (Consolidated Standards of Reporting…
Fig. 1.. CONSORT (Consolidated Standards of Reporting Trials) flow chart of randomization and clinical trial progress. *Patients redrawn from intention-to-treat analysis. †Patients redrawn from per protocol analysis. ‡Excluded from per protocol and intention-to-treat analysis because they became pregnant during treatment and had not yet undergone loop electrosurgical excision procedure (LEEP). HSIL, high-grade squamous intraepithelial lesion.
Fonseca. Topical Imiquimod for HSIL of the Cervix. Obstet Gynecol 2021.
Fig. 2.. Disposable brush.
Fig. 2.. Disposable brush.
Fonseca. Topical Imiquimod for HSIL of the Cervix. Obstet Gynecol 2021.
Fig. 3.. Application of the imiquimod immunomodulator…
Fig. 3.. Application of the imiquimod immunomodulator to the cervix. Beginning of the application (A); imiquimod reaching the entire transformation zone (B); imiquimod covering all lesion and transformation zone (C).
Fonseca. Topical Imiquimod for HSIL of the Cervix. Obstet Gynecol 2021.
Figure
Figure
No available caption

References

    1. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. . Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. doi: 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>;2-F
    1. Martin-Hirsch PP, Paraskevaidis E, Bryant A, Dickinson HO, Keep SL. Surgery for cervical intraepithelial neoplasia. The Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD001318. doi: 10.1002/14651858.CD001318.pub2
    1. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98. doi: 10.1016/S0140-6736(06)68181-6
    1. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al. . Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284. doi: 10.1136/bmj.a1284.PMID:18801868
    1. Conner SN, Cahill AG, Tuuli MG, Stamilio DM, Odibo AO, Roehl KA, et al. . Interval from loop electrosurgical excision procedure to pregnancy and pregnancy outcomes. Obstet Gynecol 2013;122:1154–9. doi: 10.1097/01.AOG.0000435454.31850.79
    1. Jin G, LanLan Z, Li C, Dan Z. Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis. Arch Gynecol Obstet 2014;289:85–99. doi: 10.1007/s00404-013-2955-0
    1. Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol 2000;43:S6–11. doi: 10.1067/mjd.2000.107808
    1. Slade HB, Owens ML, Tomai MA, Miller RL. Imiquimod 5% cream (Aldara). Expert Opin Investig Drugs 1998;7:437–49. doi: 10.1517/13543784.7.3.437
    1. Miller RL, Gerster JF, Owens ML, Slade HB, Tomai MA. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int J Immunopharmacol 1999;21:1–14. doi: 10.1016/s0192-0561(98)00068-x
    1. Bornstein J, Bentley J, Bosze P, Girardi F, Haefner H, Menton M, et al. . 2011 colposcopic terminology of the International Federation for cervical pathology and colposcopy. Obstet Gynecol 2012;120:166–72. doi: 10.1097/AOG.0b013e318254f90c
    1. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol 2010;115:1063–70. doi: 10.1097/AOG.0b013e3181d9d421
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. doi: 10.1016/j.jbi.2008.08.010
    1. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v4.03. National Cancer Institute; 2010.
    1. Grimm C, Polterauer S, Natter C, Rahhal J, Hefler L, Tempfer CB, et al. . Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol 2012;120:152–9. doi: 10.1097/AOG.0b013e31825bc6e8
    1. U.S. Food and Drug Administration. Drugs@FDA: FDA-approved drugs. Accessed December 19, 2019.
    1. Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blinded study. Gynecol Oncol 2007;107:219–22. doi: 10.1016/j.ygyno.2007.06.003
    1. van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, et al. . Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med 2008;358:1465–73. doi: 10.1056/NEJMoa072685
    1. Buck HW, Guth KJ. Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream. J Low Genit Tract Dis 2003;7:290–3. doi: 10.1097/00128360-200310000-00011
    1. Tainio K, Jakobsson M, Louvanto K, Kalliala I, Paavonen J, Nieminen P, et al. . Randomised trial on treatment of vaginal intraepithelial neoplasia-Imiquimod, laser vaporisation and expectant management. Int J Cancer 2016;139:2353–8. doi: 10.1002/ijc.30275
    1. Lawrie TA, Nordin A, Chakrabarti M, Bryant A, Kaushik S, Pepas L. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia. The Cochrane Database of Systematic Reviews 2016, Issue xx. Art. No.: CD011837. doi: 10.1002/14651858.CD011837.pub2
    1. de 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;139:377–84. doi: 10.1016/j.ygyno.2015.08.018
    1. Tristram A, Hurt CN, Madden T, Powell N, Man S, Hibbitts S, et al. . Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT(3)VIN): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2014;15:1361–8. doi: 10.1016/S1470-2045(14)70456-5
    1. Policiano AC, Lopes JP, Barata SA, Colaco AM, Calhaz-Jorge C. Topical therapy with imiquimod for vaginal intraepithelial neoplasia: a case series. J Low Genit Tract Dis 2016;20:e34–6. doi: 10.1097/LGT.0000000000000214
    1. Preti M, Igidbashian S, Costa S, Cristoforoni P, Mariani L, Origoni M, et al. . VIN usual type-from the past to the future. Ecancermedicalscience 2015;9:531. doi: 10.3332/ecancer.2015.531
    1. Tranoulis A, Laios A, Mitsopoulos V, Lutchman-Singh K, Thomakos N. Efficacy of 5% imiquimod for the treatment of Vaginal intraepithelial neoplasia-A systematic review of the literature and a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2017;218:129–36. doi: 10.1016/j.ejogrb.2017.09.020
    1. Haidopoulos D, Diakomanolis E, Rodolakis A, Voulgaris Z, Vlachos G, Intsaklis A. Can local application of imiquimod cream be an alternative mode of therapy for patients with high-grade intraepithelial lesions of the vagina? Int J Gynecol Cancer 2005;15:898–902. doi: 10.1111/j.1525-1438.2005.00152.x
    1. Koeneman MM, Kruse AJ, Kooreman LFS, Zur Hausen A, Hopman AHN, Sep SJS, et al. . TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer 2016;16:132. doi: 10.1186/s12885-016-2187-3
    1. Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, et al. . Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol 2012;206:42 e1–7. doi: 10.1016/j.ajog.2011.06.105
    1. Lin CT, Qiu JT, Wang CJ, Chang SD, Tang YH, Wu PJ, et al. . Topical imiquimod treatment for human papillomavirus infection in patients with and without cervical/vaginal intraepithelial neoplasia. Taiwan J Obstet Gynecol 2012;51:533–8. doi: 10.1016/j.tjog.2012.09.006
    1. Koeneman MM, Kruse AJ, Kooreman LF, Zur Hausen A, Hopman AH, Sep SJ, et al. . Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial. BMC Cancer 2017;17:110. doi: 10.1186/s12885-017-3108-9
    1. Sun XG, Ma SQ, Zhang JX, Wu M. Predictors and clinical significance of the positive cone margin in cervical intraepithelial neoplasia III patients. Chin Med J (Engl) 2009;122:367–72.
    1. Panna S, Luanratanakorn S. Positive margin prevalence and risk factors with cervical specimens obtained from loop electrosurgical excision procedures and cold knife conization. Asian Pac J Cancer Prev 2009;10:637–40.
    1. Costa S, De Nuzzo M, Terzano P, Santini D, De Simone P, Bovicelli A, et al. . Factors associated with cone margin involvement in CIN patients undergoing conization-equivalent electrosurgical procedure. Acta Obstet Gynecol Scand 2000;79:586–92.
    1. O'Shea AS S CK. The impact of LEEP margin status on subsequent abnormal cervical cytology. Proc Obstet Gynecol 2014;4:1–8. doi: 10.17077/2154-4751.1249
    1. Wouters T, Hendriks N, Koeneman M, Kruse AJ, van de Sande A, van Beekhuizen HJ, et al. . Systemic adverse events in imiquimod use for cervical intraepithelial neoplasia—a case series. Case Rep Womens Health 2019;21:e00105. doi: 10.1016/j.crwh.2019.e00105
    1. Borst C, Grimm C, Tanew A, Radakovic S. Imiquimod-induced effluvium after intravaginal application for treatment of cervical intraepithelial neoplasia. JAAD Case Rep 2019;5:602–4. doi: 10.1016/j.jdcr.2019.04.015

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