title: TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5% cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities.
  
  
  METHODS
  The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2-3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment.
  
  
  CONCLUSIONS
  Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary.
  
  
  BACKGROUND
  EU Clinical Trials Register EU-CTR2013-001260-34 . Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171.
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands. margot.koeneman@mumc.nl.|GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. margot.koeneman@mumc.nl.
authors.forename: M M
authors.initials: MM
authors.lastname: Koeneman
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kruse
authors.affiliation: Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: L F S
authors.initials: LFS
authors.lastname: Kooreman
authors.affiliation: Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Zur Hausen
authors.affiliation: GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Molecular Cell Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: A H N
authors.initials: AHN
authors.lastname: Hopman
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: S J S
authors.initials: SJS
authors.lastname: Sep
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Van Gorp
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: B F M
authors.initials: BFM
authors.lastname: Slangen
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: van Beekhuizen
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van de Sande
authors.affiliation: Department of Obstetrics and Gynaecology, Meander Medical Center, Amersfoort, The Netherlands.
authors.forename: C G
authors.initials: CG
authors.lastname: Gerestein
authors.affiliation: Department of Obstetrics and Gynaecology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Post box 5800, 6202 AZ, Maastricht, The Netherlands.|GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: R F P M
authors.initials: RFPM
authors.lastname: Kruitwagen
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077271:Imiquimod; D008875:Middle Aged; D060787:Neoplasm Grading; D000073718:Pancreatitis-Associated Proteins; D011788:Quality of Life; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D000077271:Imiquimod