Scolaris Content Display Scolaris Content Display

Levonorgestrel‐releasing intrauterine system for endometrial hyperplasia

Esta versión no es la más reciente

Contraer todo Desplegar todo

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of the levonorgestrel intrauterine system (LNG‐IUS) for treatment of endometrial hyperplasia (EH) with or without atypia.

Background

Description of the condition

Endometrial hyperplasia (EH) is a condition of excessive production of cells in the endometrium (inner lining of the womb) and is a precursor to the development of endometrial cancer. Endometrial cancer (EC) is the sixth most common cancer in women globally (Ferlay 2017). A recent Cochrane Library editorial highlighted the increasing rates of EC and the urgent need for research into its etiology, screening, prevention, and treatment (Crosbie 2014).

In women of reproductive age, in the absence of ovulation, the endometrium is exposed to continuous oestrogen which can lead to EH (Kurman 2011). Obesity is a leading risk factor for EH and EC in premenopausal women with abnormal uterine bleeding (Wise 2016). Obesity is associated with complex alterations in hormonal and metabolic factors, and prolonged and constant production of oestrogen from adipose tissue results in EH. Obesity during menopause also produces a state of excess oestrogen production. This results from peripheral conversion of androgens to estrogens in adipose (fat) tissues (Landrum 2012).

Although ultrasound can be used to investigate abnormal uterine bleeding, it is primarily used to look for benign pathology such as polyps or fibroids. In addition, thickened endometrium can be reported as suspicious for EH. However, EH is a histological diagnosis, meaning a pathologist needs to make the diagnosis by looking down a microscope at a sample of endometrial tissue. Endometrial biopsy can be performed by pipelle (Pipelle De Cornier®, Laboratoire CCD, France) in the outpatient or clinic setting, or by sharp curettage, a procedure that occurs in an operating theatre usually under general anaesthesia. The two diagnostic tests perform equivalently. Canadian guidelines recommend that office endometrial biopsy replace dilation and curettage as the initial assessment of the endometrium, and NICE guidelines recommend that dilatation and curettage alone should not be used as a diagnostic tool. They further state that hysteroscopy should be used only when ultrasound results are inconclusive (NICE 2016; Singh 2013).

The important distinction in the evaluation of EH is whether or not nuclear atypia is present. The new World Health Organization (WHO) classification differentiates "hyperplasia without atypia" and "atypical hyperplasia/endometrioid intraepithelial neoplasia" (Zaino 2014). It simplifies the previous 1994 classification (Scully 1994), and is based on a new understanding of molecular genetic changes. Atypical hyperplasia can progress to EC in more than one quarter of women (Anastasiadis 2000; Kurman 1985; Lacey 2010), and is associated with co‐existent EC in up to half of women (Giede 2008; Trimble 2006). If identified in a timely manner, EH can usually be successfully treated. Treatment can be medical or surgical depending on several factors, such as whether atypia is present or absent.

Description of the intervention

The levonorgestrel intrauterine system (LNG‐IUS) may be used as an alternative treatment in women with EH without atypia (vs. non‐intrauterine progestogens) or as an alternative treatment in women with atypical EH (vs. surgery). The LNG‐IUS is a small plastic T‐shaped device that fits inside the womb. The progestin levonorgestrel is a chemical derivative of 19‐nortestosterone. LNG‐IUS is a slow‐release device that provides LNG direct to the endometrium at a rate of 20 µg per 24 hours, and can remain in situ for five years or more.

Standard treatment for EH without atypia is medical therapy, traditionally in the form of high dose oral or intramuscular progestogens (such as medroxyprogesterone acetate (MPA), norethisterone, or megestrol) taken continuously for six months (RCOG 2016). Lifestyle change, such as weight loss, is also advised. Progestogens can reverse the pathological changes in the endometrium. According to the Medsafe data sheet on MPA, progestogen side effects include but are not limited to: fluid retention, unscheduled bleeding/spotting, depression, breast tenderness, headache, and decreased libido (Pfizer 2016).

Standard treatment for atypical EH is surgical therapy in the form of total hysterectomy (removal of uterus and cervix) (Landrum 2012). Only surgery is definitive, in that it completely removes the risk of progression of disease from hyperplasia to cancer. However, medical therapy may be appropriate in women who wish to retain their fertility, in women who prefer to avoid surgery, or in women who are at high risk for complications during surgery or general anaesthesia due to medical problems or obesity.

There are some potential side effects and complications from LNG‐IUS as well. The Canadian guidelines on LNG‐IUS treatment for abnormal uterine bleeding suggest that device‐related risks such as expulsion, perforation and pelvic inflammatory disease, are uncommon (Singh 2013). In a meta‐analysis of trials that compared LNG‐IUS to oral progestogens to treat EH, up to 35% of women experienced irregular bleeding/spotting in the first three months of use, decreasing to 4% later on (Abu Hashim 2015). In a Cochrane review of LNG‐IUS to treat heavy menstrual bleeding compared to other treatments, LNG‐IUS was associated with side effects such as pelvic pain/cramping, and hormonal effects such as breast tenderness, ovarian cysts, weight gain, and acne (Lethaby 2015).

How the intervention might work

The development of EC is closely linked to unopposed oestrogen exposure of the endometrium. The intrauterine administration of the progestin levonorgestrel results in extensive decidualisation of endometrial stromal cells, atrophy of the glandular and surface epithelium, and changes in vascular morphology. These changes result in markedly decreased menstrual blood loss and immediate and intense suppression of the endometrium (Guttinger 2007).

LNG‐IUS is used effectively for many clinical indications, including but not limited to: contraception, the treatment of heavy menstrual bleeding (Lethaby 2015; Sangkomkamhang 2013), and endometrial protection in women with breast cancer on adjuvant tamoxifen (Dominick 2015). It was extrapolated that it could also be used effectively to reverse the endometrial changes of hyperplasia.

Several observational studies have shown that LNG‐IUS used in women with atypical EH results in histologic regression of disease, as assessed on endometrial biopsy or hysterectomy specimens. A 2010 systematic review identified 24, mostly low quality studies, that compared histological disease regression rates between oral progestogens and LNG‐IUS (Gallos 2010). Limiting the meta‐analysis to controlled studies (389 women), the study authors found that LNG‐IUS achieved a higher histologic regression rate when compared oral progestogens for complex (pooled rate; 92% versus 66% ) and atypical hyperplasia (90% versus 69%). Additional observational studies published since 2010 show similar results (Gallos 2013; Morelli 2013; Vilos 2011).

Why it is important to do this review

This review follows and expands a Cochrane Review published in 2013 on LNG‐IUS for atypical EH (Luo 2013), and will add the management of EH without atypia. Luo 2013 did not find any randomised controlled trials (RCTs) in the literature search.

For women with hyperplasia without atypia, women may prefer insertion of LNG‐IUS to oral progestogen to lessen the side effect profile and to avoid taking daily tablets. For women with atypical hyperplasia, medical therapy may be appropriate in individualised cases of women who wish to retain their fertility, or in women who wish to avoid surgery or where surgery is deemed to be high risk. Insertion of LNG‐IUS may be an appropriate therapy instead of oral progestogen in this scenario. However, there is not yet a standard of care for duration of treatment and appropriate follow‐up (Luo 2013; Trimble 2006).

Objectives

To assess the effectiveness and safety of the levonorgestrel intrauterine system (LNG‐IUS) for treatment of endometrial hyperplasia (EH) with or without atypia.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs). Published and unpublished RCTs will be eligible for inclusion. We will exclude non‐randomised studies (e.g. studies with evidence of inadequate sequence generation, such as alternate days or patient numbers) as they are associated with a high risk of bias. We will include crossover trials but we will only include data from the first phase in meta‐analyses.

Types of participants

  • Women with a histological diagnosis of endometrial hyperplasia (EH) with or without atypia, confirmed by pipelle biopsy or curettage.

We will exclude the following types of participants.

  • Women with contraindications to the levonorgestrel intrauterine system (LNG‐IUS) (e.g. acute genital tract inflammatory disease, genital bleeding of unknown aetiology, pregnancy or suspicion of pregnancy, hypersensitivity to any component of this product, congenital or acquired uterine anomaly, known or suspected breast cancer, known or suspected uterine and cervical neoplasia or unresolved or abnormal Pap smear, acute liver disease or liver tumour).

  • Women with concurrent endometrial cancer (EC).

  • Women with a history of a hormone‐dependent malignancy (e.g. breast cancer).

  • Women taking tamoxifen.

Types of interventions

Intervention

  • LNG‐IUS (Levonova®/Mirena®, Femilis®, Fibroplant®, Mirena®, Jaydess®).

Comparator

  • Non‐intrauterine progestogens (including but not limited to: medroxyprogesterone acetate; megestrol acetate; 17a‐hydroxyprogesterone caproate; 6,17 adimethyl‐6‐dehydroxyprogesterone; 6‐methyl‐6‐dehydroxyprogesterone acetate).

  • Placebo.

  • Surgery (including but not limited to hysterectomy).

Types of outcome measures

Primary outcomes

  • Regression (complete or partial) of EH on subsequent biopsy or final histology: we define a 'complete regression' as a return of EH to normal, often with associated secretory glandular changes and atrophy; we define a 'partial regression' as a change from atypical to non‐atypical hyperplasia. If provided, we will present regression as an overall pooled hazard ratio (HR). In addition, we will present pooled HRs at different time points. The regression rate includes the complete and partial regression rates. We will consult a statistician to see if we can perform a time‐to‐event analysis using the data available. If these data are unavailable, then we will present regression as a dichotomous outcome based on length of follow‐up (short = less than six months; medium = six months up to one year; long = one year or more).

  • Adverse effects associated with LNG‐IUS device (such as: pelvic inflammatory disease; device expulsion; uterine perforation).

Secondary outcomes

  • Proportion of women undergoing hysterectomy (histologically indicated or non‐histologically indicated).

  • Proportion of women with specific individual adverse effects associated with hormones (such as: unscheduled bleeding/spotting, pelvic pain, breast tenderness, ovarian cysts, weight gain, acne).

  • Withdrawal from treatment because of adverse effects.

  • Satisfaction with treatment.

  • Cost or resource use.

Search methods for identification of studies

We will search for all published and unpublished RCTs of levonorgestrel‐releasing intrauterine system for EH, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGFG) Information Specialist.

Electronic searches

We will search the following electronic databases, trial registers and websites, from the inception of the database to present.

  • The CGF Specialised Register of Controlled Trials (Appendix 1), the Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2), MEDLINE (Appendix 3), Embase (Appendix 4), PsycINFO (Appendix 5), and CINAHL (Appendix 6). We will combine the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0 chapter 6, 6.4.11) (Lefebre 2011). The Embase, PsycINFO and CINAHL searches are combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/methodology/filters.html#random).

Other electronic sources of trials that we will search will include the following.

Searching other resources

We will handsearch reference lists of articles retrieved by the search and contact experts in the field to obtain additional data. Also we will handsearch relevant journals and conference abstracts that are not covered in the CGFG register, in liaison with the Information Specialist. Furthermore we will check ProQuest Dissertations & Theses for relevant unpublished papers.

Data collection and analysis

Selection of studies

Two review authors (MW and CC) will independently screen the titles and abstracts retrieved by the search, and we will retrieve the full‐text articles of all potentially eligible studies. Two review authors (MW and CC) will independently examine these full‐text articles for compliance with the inclusion and exclusion criteria, and select eligible studies. We will correspond with study investigators, as required, to clarify study eligibility. We will resolve any disagreements regarding study eligibility by discussion or by consulting a third review author (CF). We will list all articles excluded after full‐text assessment in a 'Characteristics of excluded studies' table with their reasons for exclusion. We will document the selection process with a PRISMA flow chart.

Data extraction and management

Two review authors (CF and CC) will independently extract data from eligible studies using a data extraction form designed and pilot‐tested by the review authors. We will resolve any disagreements by discussion or by consulting a third review author. We will extract data on the study characteristics and outcome data. Where studies have multiple publications we will collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review, and such studies will have a single study ID with multiple references.

We will correspond with study investigators for further data on methods and/or results, as required.

Assessment of risk of bias in included studies

Two review authors (MW and CC) will independently assess the included studies for risk of bias using the Cochrane 'Risk of bias' assessment tool to assess: selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition (incomplete outcome data); reporting (selective reporting); and other bias (Higgins 2011). We will resolve any disagreements by discussion or by consulting a third review author. We will describe all judgements fully and present the conclusions in the 'Risk of bias' table, which we will incorporate into the interpretation of review findings by means of sensitivity analyses.

Regarding blinding, for the objective measure of regression, if the pathologists reading the slides (outcome assessors) are aware of the type of treatment the patient is on, or it is not stated whether they are blinded, then we will rate this as at high risk of bias. For subjective measures, such as adverse effects and satisfaction, if the patients are aware of the type of treatment they are on, and there is no placebo arm to the trial, then we will rate this as at high risk of bias.

For incomplete outcome data, we will rate data missing for less than 5% of participants and balanced across groups as at low risk of bias; data missing for 5% to 15% of participants and balanced across groups as at unclear risk of bias; and data missing for greater than 15% of participants or unbalanced across groups rated as at high risk of bias.

Regarding selective reporting, if the study authors have a published protocol on a trials register to which they adhere (with respect to outcomes) and if they prospectively report adverse events, we will rate this as at low risk of bias. Otherwise we may rate them as at unclear risk (e.g. if they have no protocol or do not prospectively report adverse events) or at high risk (e.g. if they have a registered protocol but change the outcomes).

Measures of treatment effect

For regression, we will calculate HRs if the study authors provide raw data and this is possible to do. For dichotomous data, we will use the numbers of events in the control and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (ORs). For continuous data (e.g. satisfaction), if all studies report exactly the same outcomes we will calculate mean difference (MDs) between treatment groups; if similar outcomes are reported on different scales, we will calculate the standardised mean difference (SMD). We will reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We will treat ordinal data (e.g. quality of life scores) as continuous data. We will present 95% confidence intervals for all outcomes. Where data to calculate ORs or MDs are not available, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We will compare the magnitude and direction of effect reported by studies with how we present them in the review, taking account of legitimate differences.

Unit of analysis issues

The primary analysis will be per woman randomised. We will only include first‐phase data from crossover trials.

Dealing with missing data

For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat (ITT) basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If data are unobtainable and ITT analysis is not possible, we will analyse only the available data.

Assessment of heterogeneity

We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity by the measure of the I² statistic. We will consider an I² statistic measurement greater than 50% to indicate substantial heterogeneity (Higgins 2011).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we will aim to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there are 10 or more studies in an analysis, we will use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

We will perform statistical analyses using Review Manager 5 (RevMan 5) (RevMan 2014). We will combine data from primary studies using a fixed‐effect model in the comparison of LNG‐IUS versus non‐intrauterine progestogen, placebo, or surgery.

We will display an increase in the hazard of a particular outcome that may be beneficial (e.g. regression) graphically in the meta‐analyses to the right of the centre‐line and a decrease in the hazard of a particular outcome to the left of the centre‐line.

Subgroup analysis and investigation of heterogeneity

We will subgroup the primary analysis by dose of progestogen in the control group. Where data are available, we will conduct additional subgroup analysis by the following.

  • Duration of treatment (short or long).

  • Dose of LNG‐IUS [standard (20 µg levonorgestrel released daily) or low (anything less than 20µg daily release)]

If we detect substantial heterogeneity (an I² statistic value of greater than 50%), we will use subgroup and sensitivity analyses to explore possible explanations, such as clinical differences between the studies (e.g. women's age, menopausal status, body mass index, weight, histology subtype (simple or complex)). We will take any statistical heterogeneity into account when we interpret the results, especially if there is any variation in the direction of effect.

Sensitivity analysis

We will conduct sensitivity analyses for the primary outcome (pooled HRs of regression at different time points) to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed if the following occurred.

  • We restricted eligibility to studies at low risk of bias (defined as studies that rated as at low risk of bias with respect to sequence generation and allocation concealment, and not rated as at high risk of bias in any of the domains assessed).

  • We adopted a random‐effects model.

  • The summary effect measure had been the relative risk rather than the HR.

Quality of the evidence: 'Summary of findings' table

We will prepare a 'Summary of findings' table using GRADEpro software (GRADEpro GDT 2014), and Cochrane methods (Higgins 2011). This table will evaluate the overall quality of the body of evidence for the primary outcomes (regression, adverse events associated with device) in the comparison of LNG‐IUS versus non‐intrauterine progestogen (main comparison). Also we will present the comparisons of LNG‐IUS vs. surgery, and LNG‐IUS vs. placebo in the analyses and 'Summary of findings' tables. We will assess the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness, and publication bias). Two review authors will independently determine the evidence quality (as either high, moderate, low, or very low), and we will resolve any disagreements by discussion between the review authors. We will justify, document, and incorporate judgements into our reporting of results for each outcome.