Description of the condition
Endometrial cancer is a cancer of the lining of the womb. Worldwide it is the fifth most common cancer in women up to 64 years of age, and it is a common cause of death from gynaecological cancers worldwide. A woman's risk of developing endometrial cancer by age 65 years ranges from 0.46% in developing countries to 0.92% in developed countries (Globocan 2008). The incidence of endometrial cancer is steadily rising, and risk factors include an aging population, obesity, diabetes mellitus, nulliparity, late menopause, unopposed oestrogen intake or oestrogen-producing tumours, a history of breast cancer and the use of tamoxifen (Berek 2010). The incidence of endometrial cancer has increased by more than 40% in the United Kingdom since 1993, to 7536 cases in 2007 and 1741 deaths in 2008 (Evans 2011). Although the incidence and mortality rates of several other cancers have plateaued or decreased over the last decade, the incidence of endometrial cancer has been rising throughout Europe (Jemal 2008).
Endometrial cancer is predominantly a disease of postmenopausal women; most cases occur in women 50 years of age and older. However, only 10% to 15% of patients presenting with symptoms actually harbour an endometrial cancer, and the incidence of endometrial carcinoma among patients with perimenopausal bleeding may be even less (< 2%) (Dubinsky 2004).
Most patients (71%) present with Stage I disease (Creasman 2006) with a high overall survival (OS) rate greater than 90% (Creasman 2006). Only a small proportion of women (10%) present with advanced disease at diagnosis (FIGO Stages III and IV (staging according to the International Federation of Gynecology and Obstetrics)) and have much poorer survival (Jemal 2008). Treatment of Stage III and IV disease is individualised but usually involves a combination of surgery, radiation therapy and/or chemotherapy (Berek 2010). If the tumour is not amenable to surgery or radical radiotherapy, women are considered for systemic endocrine therapy or cytotoxic chemotherapy, with the aim of palliating symptoms, improving quality of life (QoL), delaying progression of disease and extending OS (Humber 2007).
Description of the intervention
For women with endometrial cancer, removal of the uterus (hysterectomy) along with removal of both fallopian tubes and ovaries is considered current standard treatment; other treatments include adjuvant radiotherapy and chemotherapy. Treatment of women with Stage IV endometrial cancer is individualised and is dictated by the site of metastatic disease and by symptoms related to disease sites but usually involves a combination of surgery, radiation therapy and/or chemotherapy (Berek 2010). For bulky pelvic disease, radiation therapy consisting of a combination of intracavitary and external beam radiation therapy is used. A Cochrane systematic review found insufficient evidence to suggest that hormonal treatment in any form or dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer (Kokka 2010).
Why it is important to do this review
The standard treatment for patients with disseminated endometrial cancer remains poorly defined. Women with disseminated endometrial cancer are treated with surgery, followed by chemotherapy ± radiotherapy depending on their fitness and symptoms related to disease. Surgical debulking (cytoreduction) with chemotherapy may be associated with improved outcomes in terms of survival (Bristow 2006). Studies suggest that among patients with advanced or recurrent endometrial cancer, complete cytoreduction to no gross residual disease is associated with superior overall survival outcome (Barlin 2010). It has been reported that complete salvage cytoreductive surgery for recurrent endometrial cancer is associated with prolonged post-recurrence survival compared with leaving any gross residual disease (Bristow 2006). A systematic review and meta-analysis is essential for a reliable evaluation of the potential benefits and risks of surgical cytoreduction with or without adjuvant chemotherapy and/or radiotherapy in advanced endometrial cancer.
To evaluate the effectiveness and safety of surgery and chemotherapy with or without radiotherapy for women with disseminated advanced endometrial cancer.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Adult women (18 years of age or older) diagnosed with disseminated advanced endometrial cancer.
Types of interventions
For comparison of treatment modalities:
- surgery with chemotherapy versus surgery with chemotherapy + radiotherapy; and
- chemotherapy ± radiotherapy versus surgery plus chemotherapy ± radiotherapy.
Types of outcome measures
- Overall survival (death from all causes). Survival will be assessed from the time when women are enrolled in the study.
- Disease-free survival (DFS).
- Quality of life (QoL), measured using a scale that has been validated through reporting of norms in a peer-reviewed publication.
- Adverse events (CTCAE 2006).
- Direct surgical morbidity (e.g. death within 30 days; injury to bladder, ureter, vascular, small bowel or colon), presence and complications of adhesions, febrile morbidity, intestinal obstruction, heamatoma, local infection).
- Surgically related systemic morbidity (chest infection, thromboembolic events (deep vein thrombosis and pulmonary embolism), cardiac events (cardiac ischaemias and cardiac failure), cerebrovascular accident.
- Recovery: delayed discharge, unscheduled re-admission.
- Chemotherapy toxicity.
Grades of chemotherapeutic and radiotherapeutic toxicity will be extracted and grouped as:
- haematological (leucopaenia, anaemia, thrombocytopenia, neutropenia, haemorrhage);
- gastrointestinal (nausea, vomiting, anorexia, diarrhoea, liver, proctitis);
- skin (stomatitis, mucositis, alopecia, allergy);
- neurological (peripheral and central); and
Search methods for identification of studies
Papers in all languages will be sought and translations carried out if necessary.
See Cochrane Gynaecological Cancer Group methods used in reviews.
The following electronic databases will be searched:
- The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register.
- Cochrane Central Register of Controlled Trials (CENTRAL).
The MEDLINE strategy based on terms related to the review topic is presented in Appendix 1.
For databases other than MEDLINE, we will adapt the search strategy accordingly. We will search databases from 1966 until June 2013.
We will identify all relevant articles on PubMed, and by using the 'related articles' feature, we will carry out a further search for newly published articles.
Searching other resources
Unpublished and Grey literature
We will search metaregister, Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and Gynaecologic Oncologists of Canada (http://www.g-o-c.org) for ongoing trials. If ongoing trials that have not been published are identified through these searches, we will approach the principal investigators to ask for relevant data. We will approach the major co-operative trials groups active in this area likewise.
We will handsearch reports of conferences in the following sources:
- Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologists)
- International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society)
- British Journal of Cancer
- British Cancer Research Meeting
- Annual Meeting of the European Society of Medical Oncology (ESMO)
- Annual Meeting of the American Society of Clinical Oncology (ASCO)
- BioMed (open text publisher); AACR conferences
Reference lists and Correspondence
We will check the citation lists of included studies and will contact experts in the field to identify further reports of studies.
Data collection and analysis
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to the reference management database Endnote X6.0.1, we will remove duplicates and two review authors (KG, MAM) will examine the remaining references independently. We will exclude those studies that clearly do not meet the inclusion criteria and will obtain copies of the full text of potentially relevant references. Two review authors (KG, MAM) will assess the eligibility of retrieved papers independently. We will resolve disagreements by discussion between two review authors (KG, MAM) or by appeal to a third review author (AB). We will document reasons for exclusion.
Data extraction and management
For included studies, we will abstract data as recommended in Chapter 7 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), including data on the following.
- Author, year of publication and journal citation (including language).
- Inclusion and exclusion criteria.
- Study design, methodology.
- Study population.
- Total number enrolled.
- Participant characteristics.
- Endometrial cancer details at diagnosis.
- FIGO stage.
- Histological cell type.
- Tumour grade.
- Extent of disease.
- Disease-free interval.
- Number of recurrences.
- Total number of intervention groups.
- Intervention details.
- Treatment modalities.
- Details of surgery.
- Type of surgeon (gynaeoncologist, gynaecologist, general surgeon).
- Experience of surgeon.
- Details of chemotherapy/radiotherapy.
- Cycle length.
- Details of best supportive care.
- Risk of bias in study (see later).
- Duration of follow-up.
- Outcomes－OS, DFS, QoL and adverse events.
- For each outcome: outcome definition (with diagnostic criteria if relevant).
- Unit of measurement (if relevant).
- For scales: upper and lower limits and whether high or low score is good.
- Results: number of participants allocated to each intervention group.
- For each outcome of interest: sample size and missing participants.
We will extract data on outcomes as below:
- For time to event (OS) data, we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports; if these are not reported, we will attempt to estimate them from other reported statistics using the methods of Parmar 1998;
- For dichotomous outcomes (e.g. adverse events), we will extract the number of participants in each group who experience the outcome of interest and the number of participants assessed at endpoint to estimate a risk ratio; and
- For continuous outcomes (e.g. quality of life measures), we will extract the final value and the standard deviation of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow-up to estimate the mean difference between treatment arms and its standard error.
Where possible, we will extract all data relevant to an intention-to-treat (ITT) analysis in which participants are analysed in groups to which they are assigned.
We will record the time points at which outcomes are collected and reported.
Two review authors (KG, MAM) will abstract data independently onto a data abstraction form specially designed for the review. We will resolve differences between review authors by discussion or by appeal to a third review author (AB) if necessary.
Assessment of risk of bias in included studies
We will assess the risk of bias in included RCTs in accordance with guidelines in the Cochrane Handbook for Systematic Reviews of Interventions using the Cochrane Collaboration's tool and the criteria specified in Chapter 8 (Higgins 2011). This will include assessment of:
- sequence generation;
- allocation concealment;
- blinding (restricted to blinding of outcome assessors as not possible to blind participants and health care providers to surgical intervention);
- incomplete outcome data:
- We will record the proportions of participants whose outcomes are not reported at the end of the study. We will code the satisfactory level of loss to follow-up for each outcome as follows:
- Yes, if fewer than 20% of participants are lost to follow-up and reasons for loss to follow-up are similar in both treatment arms;
- No, if more than 20% of participants are lost to follow-up or reasons for loss to follow-up are different between treatment arms; and
- Unclear, if loss to follow-up is not reported.
- selective reporting of outcomes; and
- other possible sources of bias.
Two review authors (KG, MAM) will apply the risk of bias tool independently and will resolve differences by discussion or by appeal to a third reviewer (AB). We will summarise results in both a risk of bias graph and a risk of bias summary. We will interpret results of meta-analyses in light of the findings with respect to risk of bias.
Measures of treatment effect
We will use the following measures of the effect of treatment.
- For time-to-event data, we will use the hazard ratio (HR) to compare the risk of death or disease progression in the treatment group with that in the control group.
- For dichotomous outcomes (e.g. adverse events, time-to-event data if it is not possible to use an HR), we will use the risk ratio.
- For continuous outcomes, we will use the mean difference between treatment arms if all trials measured the outcome on the same scale; otherwise standardised mean differences will be used.
Dealing with missing data
We will not impute missing outcome data for any of the outcomes. We will contact trial authors if data are missing or if only imputed data are reported to request data on outcomes only among participants who were assessed.
Assessment of heterogeneity
We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials that cannot be ascribed to sampling variation (Higgins 2003) and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If evidence of substantial heterogeneity is found, we will investigate and report the possible reasons for this.
Assessment of reporting biases
We will examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small study effects. When evidence of small-study effects is found, publication bias will be considered as only one of a number of possible explanations.
If a sufficient number of clinically similar studies are available, we will pool the results in meta-analyses. We will use adjusted summary statistics.
- For time-to-event data, we will pool HRs using the generic inverse variance facility of RevMan 5.
- For any dichotomous outcomes, we will calculate the risk ratio for each study and will then pool these.
- For continuous outcomes, we will pool the mean differences (or standardised mean differences) between treatment arms at the end of follow-up.
We will use random-effects models with inverse variance weighting for all meta-analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analyses, grouping the trials by:
- comparing chemotherapy followed by radiotherapy or no additional treatment.
We will consider factors such as age, stage and length of follow-up in interpretation of any heterogeneity.
We will perform sensitivity analyses excluding studies at high risk of bias.
We thank Jo Morrison for clinical and editorial advice, Jane Hayes for designing the search strategy and Gail Quinn and Clare Jess for their contributions to the editorial process.
Appendix 1. Medline Search Strategy
- exp Endometrial Neoplasms/
- (endometri* adj5 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma*)).mp.
- ((uter* and lining) adj5 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma*)).mp.
- 1 or 2 or 3
- exp Surgical Procedures, Operative/
- (surgery or surgical).mp.
- 5 or 6 or 7
- (debulk* or cytoreduct*).mp.
- 4 and 8 and 9
[mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
Contributions of authors
Khadra Galaal is the main author of the protocol, and Mansour Al Moundhri and Alberto D Lopes provided clinical expertise. Andrew Bryant drafted the methodological sections of the protocol. All authors agreed on the final version.
Declarations of interest
Sources of support
- No sources of support supplied
- Department of Health, UK.NHS Cochrane Collaboration Programme Grant Scheme CPG-10/4001/12