This is the protocol for a review and there is no abstract. The objectives are as follows:
To compare the effectiveness and associated morbidity of surgery with that of surgery and radiotherapy in patients with FIGO stage II endometrial cancer.
Description of the condition
Endometrial (womb) cancer is the sixth most common cancer in women worldwide (IARC 2010). Around 288,000 cases of endometrial cancer were recorded in 2008. It is the 13th most common cause of death from cancer with nearly 74,000 deaths in 2008 (IARC 2010). The highest age-standardised incidence rates of endometrial cancer were found in North America (16/100,000) and Central and Eastern Europe (15/100,000). In Western Europe the age-standardised incidence rate was 11/100,000 and in the UK specifically this was 13/100,000. The lowest rates were observed in South-Central Asia and Africa (excluding South Africa) (2/100,000) (IARC 2010).
Endometrial cancer primarily affects postmenopausal women, with a median age at diagnosis of 60 years, although it can occur in younger women as well (ACS 2005). Endometrial cancer is usually diagnosed at an early stage because of early occurrence of abnormal uterine bleeding (90%) during its natural history (Bakkum-Gamez 2008). Risk factors include postmenopausal oestrogen therapy, obesity, a high-fat diet, reproductive factors such as nulliparity, early menarche and late menopause, polycystic ovarian syndrome and tamoxifen use. Women with hereditary nonpolyposis colorectal cancer syndrome have a markedly increased risk of endometrial cancer compared with women in the general population (NCI PDQ 2012).
Ninety per cent of uterine cancers are adenocarcinomas, arising from the endometrium. The degree of spread of the tumour is classified according to the International Federation of Gynecology and Obstetrics (FIGO) staging system (Zaino 2009). Eighty per cent of women who present with endometrial cancer that has not spread beyond the uterine body have good overall survival (Bremond 2001). Despite this, certain histological subtypes (such as papillary serous carcinoma, clear cell carcinoma and carcinosarcoma), high-grade, deep myometrial invasion, spread to lymphatic or blood vessels, extrauterine disease and tumour extending to the cervix (neck of the womb), identify women with higher risk of recurrence (Bremond 2001). One in every three women who die of endometrial cancer are considered to have locally spread disease, confined to the pelvis/vagina at primary treatment (Jemal 2004).
Endometrial cancer can involve the endocervical glands or the cervical stroma. Until 2009, endometrial cancer not extending beyond the uterus was classed as stage IIA when there was endocervical glandular involvement only and stage IIB when there was cervical stromal involvement (Shepherd 1989). In 2009, the definition of stage II endometrial cancer was changed (Creasman 2009). The bulk of the evidence on the management of stage II endometrial cancer therefore refers to the old FIGO stage II disease (Shepherd 1989).
Stage II endometrial cancer accounts for approximately 5% to 15% of endometrial cancer cases and has a poorer prognosis than stage I disease (Ahmad 1989) with an approximate 75% five-year overall survival rate (Eltabbakh 1999). Cervical stromal involvement and positive lymph nodes are the strongest risk factors for lymphatic recurrence in the pelvic and para-aortic areas (Mariani 2002).
Description of the intervention
For women with endometrial cancer who have localised disease, removal of the uterus (hysterectomy) and removal of both fallopian tubes and ovaries is considered standard treatment (Amant 2005). Pelvic/para-aortic lymph node dissection with or without omental biopsy has been suggested for high-grade tumours, tumours with unfavourable histological subtypes and tumours invading the myometrium (Eltabbakh 2002). However, there are still many unanswered questions about the critical minimum number of lymph nodes that should be resected, whether the para-aortic nodes should be resected and whether the histologic subtype should determine the extent of lymphadenectomy (Zhang 2010).
Adjuvant treatments include radiotherapy and chemotherapy. Randomised trials on the use of adjuvant radiation therapy in patients with stage I disease did not show improved survival but did show reduced locoregional recurrence (Blake 2009; Creutzberg 2000).
Treatment options for stage II endometrial cancer, if cervical involvement is documented pre-operatively, include radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection. If the cervix is clinically uninvolved but extension to the cervix is documented on postoperative pathology, postoperative external pelvic radiotherapy (EBRT), brachytherapy (BRT), or both, should be considered (NCI PDQ 2012).
How the intervention might work
Several large, retrospective series have shown that radical hysterectomy and BSO with pelvic lymphadenectomy are associated with improved survival compared with simple hysterectomy (Boothby 1989; Eltabbakh 1999; Mariani 2001). In addition, the data also indicate that radical hysterectomy with lymphadenectomy alone is a curative option when the nodes are shown to be free of disease. This is important as women may be spared the side effects associated with adjuvant radiotherapy and will still have this modality available as a curative treatment in the event of recurrence. In practice, radical hysterectomy is usually used as treatment for women with overt cervical involvement, i.e. stage IIB (Holland 2008). The true value of radical surgery for stage IIA disease is not known, as this diagnosis is usually made after simple hysterectomy for disease that clinically seems to be confined to the uterine corpus (Holland 2008).
The role of radiation in the treatment of stage II endometrial cancer is uncertain. Radiotherapy has been used in combination with both types of surgery for stage II disease, however, the results have been conflicting and the data are not easily compared (Boente 1993; Cornelison 1999; Feltmate 1999; Keys 2004; Mariani 2001; Wright 2009).
Why it is important to do this review
Due to the variation in (i) the extent of surgical staging and the decision to offer adjuvant radiotherapy and (ii) the type of adjuvant radiotherapy offered for stage II endometrial cancer, some women are over treated and some are under treated (Cannon 2009). Treatment may also be influenced by certain histological features that are associated with a high risk of recurrence (Bremond 2001). Given the short- and long-term treatment-related complications associated with these treatment modalities, it is necessary to look at the evidence to try and come up with evidence-based criteria for selecting patients with stage II disease for either radical hysterectomy or simple hysterectomy plus adjuvant radiotherapy. This will minimise unnecessary treatment and treatment-related complications. The FIGO staging for endometrial cancer was updated in 2009, but all relevant studies reported or recruited (or both) prior to the introduction of the FIGO (2009) staging, therefore the 1989 staging was used (Shepherd 1989).
To compare the effectiveness and associated morbidity of surgery with that of surgery and radiotherapy in patients with FIGO stage II endometrial cancer.
Criteria for considering studies for this review
Types of studies
All ongoing and completed single or multicentre randomised controlled trials (RCTs). If we do not identify at least one completed RCT, non-randomised studies with a concurrent comparison group will be included. Prospective and retrospective cohort studies and case series of 30 or more patients will also be included.
In order to minimise selection bias, for non-randomised studies, we will include only studies that used statistical adjustment for baseline case mix using multivariable analyses (e.g. age, grade).
Types of participants
Adult women who have FIGO stage II endometrial cancer. If a study includes women with other stages of disease, we will include the study, but will report by women with stage II disease where possible. As all trial data with survival statistics beyond two years will have begun recruitment using the old staging system, we will include women staged as stage II under the old system only (Shepherd 1989). We will also do a sensitivity analysis excluding stage IIA to assess the impact that the changes in FIGO staging have had on our conclusions.
Types of interventions
Surgery alone or surgery followed by radiotherapy. Variations in surgery: simple or radical hysterectomy (laparoscopic, vaginal or total abdominal) plus bilateral salpingo-oophorectomy with or without pelvic and/or para-aortic lymphadenectomy. Variations in radiotherapy: EBRT and/or vaginal BRT.
Types of outcome measures
Overall survival: survival until death from all causes or last follow-up. We will assess survival from the time when women were enrolled in the study.
Locoregional disease (vaginal/pelvic) and distant recurrence
Disease-free survival: the length of time after treatment during which a patient survives with no sign of the disease
Direct surgical morbidity (e.g. injury to bladder, ureter, vascular, small bowel or colon, presence and complications of adhesions, febrile morbidity, intestinal obstruction, haematoma, local infection)
Surgically related systemic morbidity (chest infection, thromboembolic events (deep vein thrombosis and pulmonary embolism), cardiac events (cardiac ischaemia and cardiac failure), cerebrovascular accident
Delayed discharge, unscheduled re-admission
Acute and late radiotherapy-related toxic side effects (Trotti 2003)
Quality of life (QOL), measured using a scale that has been validated through reporting of norms in a peer-reviewed publication (Aaronson 1993)
Search methods for identification of studies
We will seek papers in all languages and carry out translations if necessary.
We will search the following electronic databases:
Cochrane Gynaecological Cancer Collaborative Review Group Trials Register
Cochrane Central Register of Controlled Trials (CENTRAL), current issue
MEDLINE - 1946 to date
EMBASE - 1980 to date
The MEDLINE search strategy is presented in Appendix 1.
For databases other than MEDLINE, we will adapt the search strategy accordingly.
We will identify all relevant articles in PubMed and carry out a further search using the 'related articles' feature for newly published articles.
Searching other resources
Unpublished and grey literature
We will search the m etaRegister (http://www.controlled-trials.com/mrct/), Physicians Data Query (http://www.nci.nih.gov), http://www.clinicaltrials.gov and http://www.cancer.gov/clinicaltrials for ongoing trials. If ongoing trials which have not been published are identified through these searches, we will approach the principal investigators to ask for relevant data. We will likewise approach the major co-operative trials groups active in this area.
We will search conference proceedings and abstracts through ZETOC (http://zetoc.mimas.ac.uk) and WorldCat Dissertations.
We will check the citation lists of included studies, key text books and previous systematic reviews through handsearching and contact experts in the field to identify further reports of trials. We will handsearch reports of conferences in the following sources:
American Society of Radiation Oncology (ASTRO)
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)
We will also search the following websites:
Data collection and analysis
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Reference Manager orEndnote), remove duplicates and two review authors (SC and KG) will examine the remaining references independently. Those studies which clearly do not meet the inclusion criteria will be excluded and we will obtain copies of the full text of potentially relevant references. Two review authors (SC and KG) will assess the eligibility of the retrieved papers independently. Disagreements will be resolved by discussion between the two review authors and, if necessary, by a third review author (MA). We will document reasons for exclusion.
Data extraction and management
For included studies, two review authors (SC and KG) will independently abstract data on characteristics of patients (inclusion criteria, age, FIGO stage II, co-morbidity, previous treatment, number enrolled in each arm) and interventions (surgery alone or surgery followed by radiotherapy), risk of bias, duration of follow-up, outcomes and deviations from protocol onto a data abstraction form specially designed for the review.
For time-to-event (survival and disease progression) 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 the log (HR) and its standard error using the methods of Parmar 1998.
For dichotomous outcomes (e.g. adverse events or deaths if it was not possible to use a hazard ratio) we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio.
For continuous outcomes (e.g. quality of life measures), we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference between treatment arms and its standard error.
In RCTs, we will extract both unadjusted and adjusted statistics, if reported. For non-randomised studies we will report adjusted results for survival and quality of life data. Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which we will analyse participants in the groups to which they were assigned.
We will note the time points at which outcomes were collected and reported.
Assessment of risk of bias in included studies
We will assess the risk of bias in the included RCTs using The Cochrane Collaboration tool and the following criteria.
Blinding (restricted to blinding of outcome assessors since it is not possible to blind participants and personnel to whether women received radiotherapy)
Incomplete outcome data: we will record the proportion of participants whose outcomes are not reported at the end of the study; we will code a satisfactory level of loss to follow-up for each outcome as:
yes, if fewer than 20% of patients are lost to follow-up and reasons for loss to follow-up are similar in both treatment arms;
no, if more than 20% of patients are lost to follow-up or reasons for loss to follow-up differed between treatment arms;
unclear if loss to follow-up is not reported.
Selective reporting of outcomes
Other possible sources of bias
We will assess the risk of bias in non-randomised controlled studies in accordance with four additional criteria concerning cohort selection and comparability of treatment groups:
Were there no differences between the two groups or were differences controlled for, in particular with reference to age, variations in surgery: type of hysterectomy (simple or radical), route of hysterectomy (laparoscopic, vaginal or total abdominal), pelvic and/or para-aortic lymphadenectomy, and variations in radiotherapy: external beam radiotherapy and/or vaginal brachytherapy?
Yes, if at least two of these characteristics were reported
No, if the two groups differed and differences were not controlled for
Unclear, if fewer than two of these characteristics were reported even if there were no other differences between the groups, and other characteristics were controlled for
Two review authors (SC and KG) will apply the 'Risk of bias' tool independently and resolve differences by discussion or by appeal to a third review author (MA). We will summarise results in both a 'Risk of bias' graph and a 'Risk of bias' summary. We will interpret the 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, if possible.
For dichotomous outcomes, we will use the risk ratio.
For continuous outcomes, we will use the mean difference between treatment arms.
Dealing with missing data
We will not impute missing outcome data for the primary outcome. If data are missing, or only imputed data are reported, we will contact trial authors to request data on the 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 of heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses (see below). If there is evidence of substantial heterogeneity, 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 such as publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random-effects model, we will perform further meta-analyses using fixed-effect models.
If sufficient, clinically similar studies are available, we will pool their results in meta-analyses. We will use adjusted summary statistics if non-randomised studies are included; otherwise we will use unadjusted and/or adjusted results in RCTs.
For time-to-event data, we will pool hazard ratios using the generic inverse variance facility of RevMan 5 (RevMan 2011).
For any dichotomous outcomes, we will calculate the risk ratio for each study and then pool these.
For continuous outcomes, we will pool the mean differences between the treatment arms at the end of follow-up if all trials measured the outcome on the same scale, otherwise we will pool standardised mean differences.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analyses, grouping the trials by:
We will consider factors such as age; FIGO stage II; grade; high-risk histological subtypes; clear cell, papillary serous and carcinosarcoma; and length of follow-up in the 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 contribution to the editorial process.
Appendix 1. MEDLINE search strategy
1 exp Endometrial Neoplasms/
2 ((endometr* or womb or uterine corpus or (uter* and lining)) adj5 (cancer* or tumor* or tumour* or neoplas* or carcinoma* or malignan* or adenocarcinoma*)).mp.
3 1 or 2
4 exp Gynecologic Surgical Procedures/
5 exp Lymph Node Excision/
9 (lymph* and node* and (surg* or excis* or dissect*)).mp.
12 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13 exp Radiotherapy/
19 13 or 14 or 15 or 16 or 17 or 18
20 3 and 12 and 19
21 randomized controlled trial.pt.
22 controlled clinical trial.pt.
25 clinical trials as topic.sh.
28 Comparative Study/
29 exp Cohort Studies/
30 (cohort* or prospective* or retrospective*).mp.
31 (case* and series).mp.
32 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31
33 20 and 32
[mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease suppleme
Contributions of authors
Supratik Chattopadhyay is the main author. He developed the protocol and search strategy. Khadra Galaal and Mansour Al Moundhri provided clinical expertise and designed the protocol. Andrew Bryant drafted methodological and statistical sections of the protocol.