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Comparative efficacy and complication rates after local treatment for cervical intraepithelial neoplasia and stage 1a1 cervical cancer: protocol for a systematic review and network meta-analysis from the CIRCLE Group
  1. Antonios Athanasiou1,2,
  2. Areti Angeliki Veroniki1,3,
  3. Orestis Efthimiou4,
  4. Ilkka Kalliala1,5,
  5. Huseyin Naci6,
  6. Sarah Bowden1,2,
  7. Maria Paraskevaidi1,
  8. Pierre Martin-Hirsch7,
  9. Philip Bennett1,2,
  10. Evangelos Paraskevaidis2,8,
  11. Georgia Salanti4,
  12. Maria Kyrgiou1,2
  1. 1 Department of Surgery and Cancer, Faculty of Medicine, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
  2. 2 Imperial College Healthcare NHS Trust, London, UK
  3. 3 Department of Primary Education, School of Education, Panepistimio Ioanninon, Ioannina, Greece
  4. 4 Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
  5. 5 Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  6. 6 Department of Health Policy, London School of Economics and Political Science, London, UK
  7. 7 Department of Gynaecologic Oncology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
  8. 8 Department of Obstetrics and Gynaecology, University of Ioannina and University Hospital of Ioannina, Ioannina, Greece
  1. Correspondence to Dr Maria Kyrgiou; m.kyrgiou{at}


Introduction Local treatments for cervical intraepithelial neoplasia (CIN) and microinvasive disease remove or ablate a cone-shaped part of the uterine cervix containing the abnormal cells. A trend toward less radical techniques has raised concerns that this may adversely impact the rates of precancerous and cancerous recurrence. However, there has been no strong evidence to support such claims. We hereby describe a protocol of a systematic review and network meta-analysis that will update the evidence and compare all relevant treatments in terms of efficacy and complications.

Methods and analysis Literature searches in electronic databases (CENTRAL, MEDLINE, EMBASE) or trial registries will identify published and unpublished randomised controlled trials (RCTs) and cohort studies comparing the efficacy and complications among different excisional and ablative techniques. The excisional techniques include cold knife, laser or Fischer cone, large loop or needle excision of the transformation zone and the ablative radical point diathermy, cryotherapy, cold coagulation or laser ablation. The primary outcome will be residual/recurrent disease defined as abnormal histology or cytology of any grade, while secondary outcomes will include treatment failure rates defined as high-grade histology or cytology, histologically confirmed CIN1+ or histologically confirmed CIN2+, human papillomavirus positivity rates, involved margins rates, bleeding and cervical stenosis rates. We will assess the risk of bias in RCTs and observational studies using tools developed by the Cochrane Collaboration. Two authors will independently assess study eligibility, abstract the data and assess the risk of bias. Random-effects meta-analyses and network meta-analyses will be conducted using the OR for dichotomous outcomes and the mean difference for continuous outcomes. The quality of the evidence for the primary outcome will be assessed using the CINeMA (Confidence In Network Meta-Analysis) tool.

Ethics and dissemination Ethical approval is not required. We will disseminate findings to clinicians, policy-makers, patients and the public.

PROSPERO registration number CRD42018115508.

  • Cervical intraepithelial neoplasia/therapy
  • Treatment outcome
  • Recurrence
  • Conization/adverse effects
  • Ablation techniques/adverse effects

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  • Contributors The study was conceived and designed by MK, GS and EP. The protocol was drafted by AA, MK, AAV, OE, IK, GS and was revised critically for important intellectual content by all authors (AA, AAV, OE, IK, HN, SB, MP, PM-H, PB, EP, GS, MK).

  • Funding This work is supported by National Institute for Health Research (NIHR) Research for Patient Benefits (Grant Reference Number PB-PG-0816-20004, P67307). It is also supported by the British Society of Colposcopy Cervical Pathology Jordan/Singer Award (P47773) and the Imperial College Healthcare Charity (P47907) (MK). AAV is funded by the European Union’s Horizon 2020 (No 754936). None of the funders have any influence on the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

  • Competing interests MK has received travel and conference expenses, honoraria and consultancy fees for commercial companies (Inovio, MSD, etc); these activities are not related to the project.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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