FINAL PROTOCOL: MICROWAVE AND THERMAL BALLOON ENDOMETRIAL ABLATION FOR HEAVY MENSTRUAL BLEEDING: A SYSTEMATIC REVIEW

A. This protocol is final

B. Details of the research team

Correspondence to: Ms. Ruth Garside Research Fellow, Peninsula Technology Assessment Group, Dean Clarke House, Southernhay East, Exeter EX1 1PQ
Dr. Ken Stein, Senior Lecturer in Public Health, Peninsula Technology Assessment Group (LEAD)
Dr Katrina Wyatt, Lecturer in Health Services Research, University of Exeter
Mrs Kim Dalziel. Research Fellow, Peninsula Technology Assessment Group
Dr. Ali Round, Senior Lecturer in Public Health, Peninsula Technology Assessment Group
Ms Alison Price, Information Specialist, Southampton Health Technology Assessment Centre

C. Full title of research question

What is the effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation techniques for heavy menstrual bleeding compared to transcervical resection and rollerball ablation and hysterectomy?

D. Clarification of the research question and scope

Heavy menstrual bleeding (HMB) or menorrhagia can have a major impact on women's lives. Objective menorrhagia is defined as total blood loss of more than 80ml per menstruation over several consecutive cycles.1 However, since objective measurement is difficult, other subjective methods of estimating blood loss, such as flooding, passing of clots, the numbers of pads or tampons used and haemoglobin levels, are likely to be used in clinical practice. Subjective assessment of a woman's periods and the effect that they have on her lifestyle should be taken into consideration when looking at treatment efficacies for HMB.

Menorrhagia without major pathology is a condition that affects many otherwise healthy women with one in twenty women aged 30 to 49 consulting her GP each year with menorrhagia.2 First line treatment is usually with drugs, although only 58% of women receive medical therapy before referral to a specialist.3 Once referred to a gynaecologist, 60% of women with menorrhagia will have a hysterectomy within 5 years. One in five women in the UK have a hysterectomy before the age of 60 (Coulter 1991, in RCOG Guidelines for menorrhagia in secondary care, 1998) and about half of these are for a patient complaint of menorrhagia.4 It has been estimated that up to half of all women presenting with menorrhagia will have blood loss within the normal range defined by population studies.5 Hysterectomy is the only operation carried out without a routine assessment of the organ.6

51,858 hysterectomies were performed in 2000/01 of which 82% were abdominal and the remainder vaginal.7 Of these operations at least half might be expected to be performed for menorrhagia.8

Hysterectomy is a radical solution for HMB, and there are risks of peri- and post?operative complications and, in some cases, significant emotional implications. Since the 1980s, endometrial ablation (EA) techniques have been developed as alternative, less invasive treatments for menorrhagia. All methods of endometrial destruction aim to destroy the inner lining of the uterus (endometrium). The endometrium is capable of regeneration and techniques must cause necrosis of the endometrial cells in order to suppress menstruation. This includes removing the full thickness of the uterine lining together with the superficial myometrium (underlying muscular layer), and the basal glands thought to be the focus of endometrial growth. First generation techniques such as resection, roller-ball and laser ablation require direct visualization of the endometrium using a hysteroscope.

A Cochrane review comparing endometrial resection and ablation techniques with hysterectomy has been undertaken and was updated in 1999.9 This review considers five RCTs, four comparing transcervical resection of the endometrium (TCRE) and hysterectomy and one with a three way comparison including laser EA. This will be reviewed and an updated search for relevant RCTs undertaken in order to provide additional information for the appraisal to offer a more complete overview of the ablation techniques and hysterectomy.

The Cochrane review concluded that endometrial destruction offered an alternative surgical treatment for menorrhagia to hysterectomy. Both types of procedure were considered as effective and had high satisfaction rates from women. The permanent relief that hysterectomy offers is offset by longer operating time, longer recovery period and higher rates of post-operative complications. The initial cost of endometrial destruction is significantly lower than for hysterectomy but, as a proportion of women require further surgery, this cost difference lessens over time.9

It has been suggested that newer EA techniques (such as microwave and thermal balloon endometrial ablation) have fewer complications than resection. While older style endometrial ablation techniques require specialist training and require a high level of technical skill, newer methods are regarded as quick and easy to learn.10

Technologies to be appraised
Microwave endometrial ablation (MEA) uses high frequency microwave energy to rapidly heat and destroy the endometrium. Microwaves at a frequency of around 9GHz are used and these are absorbed by the endometrial tissue to a depth of 3mm. The heat which is generated is conducted deeper into the endometrium so that tissue is destroyed to a maximum depth of 5-6mm aiming at sufficient endometrial ablation without risk to adjacent organs.

An applicator inserted into the uterine cavity through the dilated cervix delivers the microwaves. The applicator is slowly withdrawn with a sweeping movement to ensure that all of the endometrium is treated. The temperature is monitored and controlled through an external control unit. Treatment takes 5-10 minutes to complete and can be carried out under general or local anaesthetic. Medication is given to minimise cramping during and after the procedure.

Thermal ablation uses a silicone or latex balloon catheter which is inserted into the uterus through the vagina. A sterile liquid is used to inflate the balloon to fit the uterine cavity and is then heated to about 87oC and circulated within the balloon for about eight minutes causing thermal ablation of the endometrial lining. Either local or general anaesthesia may be used. Medication is given to minimise cramping during and after the procedure.

A preliminary literature review found 52 references relating to RCTs of hysterectomy versus various methods of endometrial ablation, comparing types of EA or preparatory techniques used during EA. Thirteen of these are RCTs of microwave ablation or thermal balloon ablation versus first generation techniques. However, there is likely to be repeat reporting of the same trials among these references.

Scope

All randomised and non-randomised controlled trials of microwave or thermal balloon endometrial ablation versus any removal and ablation of endometrium (by resection or roller-ball,) or hysterectomy will be included. Head to head comparisons of microwave and thermal balloon ablation will be sought. Uncontrolled studies will be excluded.

The existing Cochrane systematic review of endometrial resection and hysterectomy will be reviewed. An updated search to locate any recent RCTs of this comparison will be undertaken.

Population

All women recruited from family planning clinics, primary care or specialist clinics.

Inclusion criteria:
Studies including pre-menopausal women with regular heavy periods measured objectively or subjectively.

Exclusion criteria:
Studies including women with the following criteria will be excluded if these women cannot be separately identified:
- Post menopausal bleeding (>1 year from the last period)
- Irregular menses and intermenstrual bleeding (metrorrhagia)
- Pathological causes of menorrhagia (e.g. uterine cancer)
- Iatrogenic causes of menorrhagia (e.g. intra-uterine device)

Interventions

Microwave or thermal balloon endometrial ablation versus any removal and ablation of endometrium (including transcervical resection of the endometrium, and endometrial ablation by electrocautery or laser) or hysterectomy (by open abdominal, vaginal or laparoscopic routes).

Outcomes

• Quality of life: Women's perceived change in quality of life.
  
• Menstrual bleeding: Amenorrhoea, objective or subjective assessment of improvement in menstrual blood loss
  
• Duration of surgery
  
• Length of hospital stay
  
• Time to return to normal activities / work
  
• Rate of satisfaction: At years after surgery 1,2,3, 4.
  
• Requirement for further surgery for menstrual symptoms: At years after surgery 1,2,3,4.
  
• Adverse events: Including uterine perforation, bleeding, haematometra, laceration, air embolism, intra-abdominal injury, fluid absorption, infection, cyclical pain, pregnancy and death.
  
• Resource use / cost

Patient Preferences

Information about patient preferences for methods or treatment for menorrhagia will be taken from included studies. We will extract data on the number of women approached to participate, the number taking part and the number who expressed a preference for a particular surgery.

E. Report methods

The report will include a systematic review of the evidence for clinical effectiveness and cost-effectiveness based on clinical review and cost data from published sources. The review will be undertaken systematically following the general principles outlined in NHS CRD Report 4. The research protocol will be updated as necessary as the research programme progresses. Any changes to the protocol will be reported to NCCHTA and NICE.

Search Strategy and Inclusion Criteria
Searches for clinical efficacy will start with the Cochrane library. Where good quality relevant systematic reviews are found these will form the core of the assessment of effectiveness. Preliminary searches show that a Cochrane review for hysterectomy versus TCRE and rollerball exists and searches for this comparison will be restricted to the years since the existing review was written.

For the main research question, all publications which describe trials of microwave or thermal balloon endometrial ablation techniques versus other endometrial ablation techniques or versus hysterectomy will be obtained using the search strategy described below. Preliminary searches have shown that a Cochrane review of endometrial destruction techniques also exists. Where appropriate, any meta-analyses will be updated.

Only studies with a comparison arm will be considered for inclusion. Where RCT evidence directly addressing the questions of interest and sufficient to reach a conclusion is obtained then non-randomised studies will not be included. If insufficient RCT evidence is available non-randomised studies will be included.

Titles and abstracts will be examined for inclusion by two independent reviewers and disagreement will be resolved by consensus.

Databases:
Electronic databases: including MEDLINE (Silver Platter); PubMed (previous 6 months for latest publications); EMBASE; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, DARE, NHS EED and HTA databases; NRR (National Research Register); Web of Science Proceedings; Current Controlled Trials; Clinical Trials.gov
Bibliographies of included studies will be assessed for relevant studies.
Contacting research groups and industry

Inclusion
- Systematic Reviews
- Randomised Controlled Trials (RCTs)
- Controlled clinical trials (CCTs)

Exclusion
- Animal models
- Preclinical and biological studies
- Narrative reviews, editorials, opinions
- Non controlled studies
- Non English language papers
- Reports published as meeting abstracts only

Review methods

Data extraction strategy
Data will be extracted by one researcher and checked by another.

Quality assessment
Assessments of quality will be performed using the indicators shown below. Due to the nature of the intervention, the presence of blinding of treatment and treatment concealment are not applicable measures of quality except possibly in head to head comparisons.

Trial characteristics:
1. Appropriate method of randomisation of RCTs
2. Blind assessment of outcomes
3. Numbers of women randomized, excluded and lost to follow up.
4. Whether intent to treat analysis is performed
5. Whether a power calculation was done
6. Timing, duration and location of the study

Study participants:
1. Age and any other recorded characteristics of women in studies.
2. Inclusion criteria
3. Exclusion criteria

Interventions used:
1. Type of endometrial ablation technique and route of hysterectomy surgery
2. Endometrial thinning agents used.

Outcomes:
1. Methods used to evaluate women's satisfaction and quality of life post-surgery
2. Methods used to measure menstrual loss
3. Methods used to evaluate resource and patients costs
4. Length of follow up

Methods of analysis/synthesis
Where appropriate, meta-analysis methods will be employed to estimate a summary measure of effect, otherwise information will be synthesised by narrative methods.

Methods for evaluating quality of life, costs and cost effectiveness and/or QALYS

Quality of life measures, costs for treatments and savings will be taken from published work. Estimates of resource costs from individual trusts or groups of trusts may be used, if time permits, where published data are not available.

If an economic analysis for microwave or thermal ablation already exists we will provide a critique of this. If no economic analysis already exists, a cost effectiveness model will be undertaken of microwave and thermal ablation techniques versus TCRE and rollerball ablation and hysterectomy.

F. Handling the Industry submission

Where information provided by industry meets our inclusion criteria, this will be included in the review.

G. Project Management

Timetable
Draft Protocol: 30th July 2002
Finalised protocol: 20th August 2002
Progress report: 13th November 2002
Draft final report: 22nd January 2003

Competing interests
None

External reviewers
A group is currently being formed. This group will act as an expert resource to guide the process of the review. At least two separate experts will be identified as peer reviewers of the completed draft review.

Reference List

1. Royal College of Obstetricians and Gynaecologists. The Initial Management of Menorrhagia. Evidence Based Guidelines No. 1. London: Royal College of Obstetricians and Gynaecologists, 1998.
   
2. Vessey MP, Villard-Mackintosh L, Mcpherson K, Coulter A, Yeates D. The epidemiology of hysterectomy: findings in a large cohort study. Brit J Obstet Gynaecol 1992;99:402-7.
   
3. Coulter A, Bradlow J, Agass M, Martin-Bates C, Tulloch A. Outcomes of referrals to gynaecology out-patients clinics for menstrual problems: an audit of general practice records. Br J Obstet Gynaecol 1991;98:789-96.
   
4. Chimbira TH AATAC. Study of menstrual blood loss. Br J Obstet Gynaecol 1980;87:603-9.
   
5. Fraser IS MGMR. A preliminary study of factors influencing perception of menstrual blood loss volume. Am J Obstet Gynecol 1984;149:788-93.
   
6. Wyatt KM DPWTOP. Determination of total menstrual blood loss. Fertil Steril 2001;76:125-31.
   
7. Hospital Episode Statistics. London: Department of Health, 2001.
   
8. Coulter A, Kelland J, Long A, Melville A, O'Meara S, Sculpher M et al. The Management of Menorrhagia. Effective Health Care 1995;9.
   
9. Lethaby A, Shepperd S, Cooke I, Farquhar C. Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database.Syst Rev 2000.
   
10. Cooper KG, Bain C, Parkin DE. Comparison of microwave endometrial ablation and transcervical resection of the endometrium for treatment of heavy menstrual loss: a randomised trial. Lancet 1999;354:1859-63.