Title: Local treatment of cervical pre-invasive and early invasive disease: synthesis of the evidence and network meta-analysis on efficacy and treatment-related reproductive morbidity
Funder: Department of Health and Social Care

Abstract: Background Treatment for cervical pre-invasive and early invasive disease with conisation removes or ablates a cone-shaped part of the uterine cervix containing the abnomal cells. Although the efficacy of conisation is high, there has been increasing evidence to suggest that the risk of preterm birth is increased and that this is higher for techniques that remove larger parts of the cervix. This has led to the use of less radical treatments, while concerns have been raised, that this shift may adversely impact the rates of precancerous and cancerous recurrence. Aims and Objectives We aim to: 1. Provide patients and their clinicians with the best, up-to-date evidence about the relative efficacy and safety of the various treatment techniques so as to enable them to take informed decision 2. Develop an economic evaluation model to compare the cost-effectiveness of these techniques In order to achieve these aims, our objectives are to: 1. Identify, evaluate and synthesize the results from studies comparing different treatments with respect to the rates of pre-invasive and invasive recurrence, complications and reproductive morbidity 2. Generate a clinically useful ranking of the alternative options for treatment according to their efficacy, morbidity and cost-effectiveness in order to make recommendations and contribute to NHS guidelines for decision makers 3. Empower the national health care service consumer by providing accessible and understandable summaries of the available evidence Plan of Investigation We will search electronic databases to identify all randomised controlled trials (RCTs) and observational studies comparing the efficacy and complications including the risk of preterm birth amongst different treatment techniques as compared to untreated controls and perform a series of meta-analyses and network meta-analyses. The main outcome measures will include efficacy parameters (pre-invasive or invasive recurrence rates); fertility outcomes (total pregnancy rates); early pregnancy (24weeks) outcomes (2nd trimester miscarriage, preterm birth (PTB), preterm prelabour rupture of membranes (pPROM), low birth weight ( Risk of bias in the included RCTs will assessed as per the Cochrane Handbook of Systematic Reviews and in observational studies as per the ROBINS-I criteria. Two authors will independently search the literature, assess the eligibility, abstract the data and assess the risk of bias. We will perform meta-analyses for each comparison for which we have more than two trials using the odds ratio (OR) for dichotoumous outcomes and network meta-analyses for the studies that meet the transitivity assumption. The cost-effectiveness analysis will employ a state-transition Markov cohort model to parallel the natural course of cervical disease and to predict outcomes after different treatment techniques. Potential benefits to to patients and the NHS The quantification of the comparative efficacy and reproductive morbidity of different treatment techniques and cone lengths has become a women s health priority and demands high-quality synthesis of the evidence in accessible and understandable summaries. These should be available for effective patient counseling at colposcopy and antenatal clinics so that patients, clinicians and policy makers are able to balance the trade-off from increased reproductive morbidity with increasing treatment radicality against the quantified risk of recurrence of preinvasive and invasive cervical disease. This will further allow the identification of women at high risk of PTB that would benefit from intensive surveillance antenatally; will minimize the unnecessary interventions for those at low risk; and identify the most cost-effective treatment alternative for more efficient allocation of NHS resources.The proposed evidence synthesis will empower health care consumers and will contribute to NHS and international guidelines with data on the efficacy and risk of alternative options for treatment.

Lay abstract: Background: Precancer of the cervix (neck of the womb) is treated by removing or burning a cone-shaped part of the cervix. It has been suggested that the different local treatments for precancer of the cervix can increase the risk of having a premature birth (before 37 weeks of gestation) and a miscarriage in the second trimester. The risk is more increased for treatments that remove or burn larger parts of the cervix. This has led many doctors to remove or burn smaller parts of the cervix, but concerns have been raised that this may increase the risk of recurrent precancer and cancer. Aims: We aim to provide patients, their clinicians and policy makers with the best, up-to-date information about the efficacy, safety and cost of the various local treatments that are available for cervical precancer so as to enable them to take informed decisions. Design and Methods: We will identify all studies that compare the efficacy and complications amongst different local treatments and also to women that have not received treatment. Sophisticated statistical methods will be employed. We will also assess the balance between efficacy and cost of the alternative treatment options. Patient and public involvement: Patients and the wider public have been involved in the design of this proposal. Their involvement will continue throughout the study and will guide the priority questions to be addressed, the development of research reports in lay language. Spread of the results: The results will be published in journals that have open access to the public with a wide readership and will be presented in national and international meetings, web documents, leaflets, public presentations and media interviews. We will work closely with Jo s Trust cervical cancer charity that plays an important role in educating patient communities.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CANCER AND NEOPLASMS