Imiquimod Treatment of CIN Lesions

Summary

Rationale: Cervical Intraepithelial Neoplasia (CIN) is the premalignant condition of cervical cancer. High grade CIN (CIN 2-3) is currently treated by large loop excision of the transformation zone (LLETZ). This treatment has potential complications, such as hemorrhage, infection and preterm birth in subsequent pregnancies. For this reason, non-invasive therapies are needed. Imiquimod (an immunomodulator) was proven effective in the treatment of HPV-related vulvar intraepithelial neoplasia (VIN) and may also be effective in HPV-related CIN. \[van Seters, 2012\] However, the evidence is limited and study results are not consistent. \[Grimm, 2012; Pachman, 2012; Lin, 2012\] Objectives: Primary objectives: (1) to investigate the efficacy of imiquimod 5% cream for the treatment of CIN2-3 lesions and (2) to develop biomarker panels to predict clinical response to imiquimod therapy. Secondary objectives: to assess side effects of imiquimod treatment and LLETZ, disease recurrence and quality of life. Hypothesis: The investigators hypothesize that imiquimod will be an effective treatment modality in approximately 50-75% of CIN lesions treated without surgical intervention. Study design: Single-centre randomized controlled intervention trial. Study population: 140 women with a histological diagnosis of CIN2-3, equally divided over two study arms. Intervention: Patients will be randomized into one of two arms: 1. Imiquimod treatment arm. Patients in this group are treated by a 16-week regime of imiquimod 5% cream. 2. Standard treatment arm. LLETZ will be performed on patients in this group. Colposcopy with diagnostic biopsies will be performed after 10 weeks for the imiquimod treatment arm. In case progressive disease, the treatment will be ended and appropriate surgical excision will be performed. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies. A histological biomarker panel will be developed, consisting of markers representing both host and viral factors. Main study parameters/endpoints: The primary endpoint of the study is regression-or-not of CIN2-3, defined as CIN1 or less at the colposcopy at 20 weeks for the imiquimod arm and PAP 1 cytology at 6 months for the LLETZ group.

Timeline

Start

2014-12

Primary completion

2016-06

Completion

2016-06

Publications

• Background van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008 Apr 3;358(14):1465-73. doi: 10.1056/NEJMoa072685.
• Background Grimm 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.
• Background Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, Sloan JA, Loprinzi CL, Gostout BS. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012 Jan;206(1):42.e1-7. doi: 10.1016/j.ajog.2011.06.105. Epub 2011 Jul 13.
• Background Lin CT, Qiu JT, Wang CJ, Chang SD, Tang YH, Wu PJ, Jung SM, Huang CC, Chou HH, Jao MS, Lai CH. Topical imiquimod treatment for human papillomavirus infection in patients with and without cervical/vaginal intraepithelial neoplasia. Taiwan J Obstet Gynecol. 2012 Dec;51(4):533-8. doi: 10.1016/j.tjog.2012.09.006.
• Background Peto J, Gilham C, Deacon J, Taylor C, Evans C, Binns W, Haywood M, Elanko N, Coleman D, Yule R, Desai M. Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort. Br J Cancer. 2004 Aug 31;91(5):942-53. doi: 10.1038/sj.bjc.6602049.
• Background McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. doi: 10.1016/S1470-2045(08)70103-7. Epub 2008 Apr 11.
• Background Canfell K, Barnabas R, Patnick J, Beral V. The predicted effect of changes in cervical screening practice in the UK: results from a modelling study. Br J Cancer. 2004 Aug 2;91(3):530-6. doi: 10.1038/sj.bjc.6602002.
• Background Follen M, Atkinson EN, Schottenfeld D, Malpica A, West L, Lippman S, Zou C, Hittelman WN, Lotan R, Hong WK. A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix. Clin Cancer Res. 2001 Nov;7(11):3356-65.
• Background Meyskens FL Jr, Surwit E, Moon TE, Childers JM, Davis JR, Dorr RT, Johnson CS, Alberts DS. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst. 1994 Apr 6;86(7):539-43. doi: 10.1093/jnci/86.7.539.
• Background Keefe KA, Schell MJ, Brewer C, McHale M, Brewster W, Chapman JA, Rose GS, McMeeken DS, Lagerberg W, Peng YM, Wilczynski SP, Anton-Culver H, Meyskens FL, Berman ML. A randomized, double blind, Phase III trial using oral beta-carotene supplementation for women with high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2001 Oct;10(10):1029-35.
• Background Alvarez RD, Conner MG, Weiss H, Klug PM, Niwas S, Manne U, Bacus J, Kagan V, Sexton KC, Grubbs CJ, Eltoum IE, Grizzle WE. The efficacy of 9-cis-retinoic acid (aliretinoin) as a chemopreventive agent for cervical dysplasia: results of a randomized double-blind clinical trial. Cancer Epidemiol Biomarkers Prev. 2003 Feb;12(2):114-9.
• Background Garcia F, Petry KU, Muderspach L, Gold MA, Braly P, Crum CP, Magill M, Silverman M, Urban RG, Hedley ML, Beach KJ. ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2004 Feb;103(2):317-26. doi: 10.1097/01.AOG.0000110246.93627.17.
• Background Van Pachterbeke C, Bucella D, Rozenberg S, Manigart Y, Gilles C, Larsimont D, Vanden Houte K, Reynders M, Snoeck R, Bossens M. Topical treatment of CIN 2+ by cidofovir: results of a phase II, double-blind, prospective, placebo-controlled study. Gynecol Oncol. 2009 Oct;115(1):69-74. doi: 10.1016/j.ygyno.2009.06.042. Epub 2009 Aug 3.
• Background Kaufmann AM, Nieland JD, Jochmus I, Baur S, Friese K, Gabelsberger J, Gieseking F, Gissmann L, Glasschroder B, Grubert T, Hillemanns P, Hopfl R, Ikenberg H, Schwarz J, Karrasch M, Knoll A, Kuppers V, Lechmann M, Lelle RJ, Meissner H, Muller RT, Pawlita M, Petry KU, Pilch H, Walek E, Schneider A. Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer. 2007 Dec 15;121(12):2794-800. doi: 10.1002/ijc.23022.
• Background Trimble CL, Piantadosi S, Gravitt P, Ronnett B, Pizer E, Elko A, Wilgus B, Yutzy W, Daniel R, Shah K, Peng S, Hung C, Roden R, Wu TC, Pardoll D. Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype. Clin Cancer Res. 2005 Jul 1;11(13):4717-23. doi: 10.1158/1078-0432.CCR-04-2599.
• Background Munk AC, Gudlaugsson E, Ovestad IT, Lovslett K, Fiane B, Hidle Bv, Kruse AJ, Skaland I, Janssen EA, Baak JP. Interaction of epithelial biomarkers, local immune response and condom use in cervical intraepithelial neoplasia 2-3 regression. Gynecol Oncol. 2012 Dec;127(3):489-94. doi: 10.1016/j.ygyno.2012.09.010. Epub 2012 Sep 24.
• Koeneman MM, Kruse AJ, Kooreman LF, Zur Hausen A, Hopman AH, Sep SJ, Van Gorp T, Slangen BF, van Beekhuizen HJ, van de Sande AJ, Gerestein CG, Nijman HW, Kruitwagen RF. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial. BMC Cancer. 2017 Feb 7;17(1):110. doi: 10.1186/s12885-017-3108-9.
• Koeneman 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.

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