Comparative efficacy and reproductive outcomes after fertility-sparing treatment for endometrial hyperplasia, with or without atypia, and early endometrial cancer: synthesis of the evidence and network meta-analysis

Research question Which fertility-sparing treatment for endometrial cancer (EC) is the most effective within 6 months? Background One fifth of ECs (around 2000/year in the UK) are found in pre-menopausal women, many of whom may not yet have completed their families. Routine treatment of EC, and often its precursor endometrial hyperplasia (EH) involves a hysterectomy, whereas fertility-sparing treatments (FSTs), allow women to retain their uterus and carry a pregnancy. FST usually involves progesterone-based therapies delivered orally or intrauterine, which can also be combined with other treatments including hysteroscopic resection. Although there is evidence to support the effectiveness of FSTs, there are no prospective randomised controlled trials comparing the efficacies of oral to intrauterine progesterones. As such, international clinical guidelines are limited in their scope to guide clinicians managing these patients. Network-meta analysis (NMA) is a methodological vehicle that facilitates production of both direct evidence, where studies compare two treatments head to head, and indirect evidence, where a third intermediate comparator can be used to compare two treatments that have not been directly compared. There is currently an unmet need to provide patients and clinicians with accurate comparative information on the different FSTs to allow for enhanced and personalised decision making. Aims and Objectives Aims: Provide an up-to-date evidence summary about the relative efficacy and safety of all accepted FSTs for EH with or without atypia, and EC. Outcomes will include: a. Oncological outcomes, including regression b. Reproductive outcomes, including pregnancy, miscarriage, and live birth c. Tolerability outcomes Objectives: 1. Identify all relevant studies where the efficacy, safety and reproductive outcomes of FSTs for EH and EC have been compared 2. Evaluate the data using a meta-analysis (MA) and NMA framework 3. Generate a clinically meaningful summary of this evidence Methods We will perform a librarian-reviewed, systematic search of electronic databases, to identify all RCTs and observational studies comparing the oncological and reproductive outcomes amongst different FSTs for EC, and EH with and without atypia. We will extract data and perform risk of bias assessments independently and in duplicate. Under the supervision of experienced statisticians, we will perform a series of random-effects NMA in R. Timelines for delivery Year 1 Months 1-3: Team appointment Finalise protocol Search strategy PPI group formation Months 4-6: Searches Data extraction PPI meeting to discuss priorities Months 7-9 months: Data processing Months 10-12: Begin meta-analysis Year 2 Months 1-3: Network meta-analysis PPI group meeting Months 4-6: Sub-analyses/sensitivity analyses Manuscript preparation Months 7-9: Presentation Final PPI meeting Months 10-12: Submission of manuscript Guideline integration Anticipated Impact and Dissemination Women who are faced with a choice of hysterectomy or FSTs will be provided with summary statistics, facilitating an informed and patient-centred decision. Women will be able to opt for a FST that best suits their individual needs, based on both the oncological safety and likelihood of achieving a pregnancy and live birth. We will disseminate our findings in at international conferences, and work together with committees of these societies to produce up-to-date guidelines, based on this evidence.