Description of the condition
Cancer is a leading cause of death worldwide (WHO 2008). Gynaecological cancers (i.e. cancers affecting the ovaries, uterus, cervix, vulva, and vagina) are among the most common cancers in women. Globally, a woman's risk of developing cancer of the cervix, ovaries, and uterus by the age of 65 is 2.2%; cancers of the vulva and vagina are less common. Gynaecological cancers account for 25% of all new cancers diagnosed amongst women up to 65 years of age in developing countries, compared with 16% in the developed world (GLOBOCAN 2008).
Uterine cancer tends to be a disease of the elderly and obese female population. More than 80% of these cases arise from the endometrium. Endometrial cancer is the most common genital tract cancer among women in developed countries. The worldwide risk of a woman developing cancer of the uterus by the age of 65 is 0.59%, and the rate is twice as high in developed countries compared with developing countries (GLOBOCAN 2008). The cornerstone of treatment of women with endometrial cancer is surgery, followed, in some patients, by radiotherapy with or without chemotherapy. The prognosis for women with early-stage disease is good, and many women are cured by surgery alone. Women presenting with advanced or recurrent disease have a much poorer prognosis, with a median overall survival of 9 to10 months (Thigpen 2001; Thigpen 2004).
Cervical cancer is the second most common cancer among women up to 65 years of age, and it is the most frequent cause of death from gynaecological cancers worldwide; its incidence is twice as high in developing countries, where women often present with advanced-stage disease (GLOBOCAN 2008). Over the past three decades, it has become apparent that the main risk factor for the development of cervical cancer is persistent infection by the human papillomavirus (HPV). More than 100 subtypes of HPV are known; the subtypes at greatest risk for forming cancer are subtypes 16 and 18, which are responsible for most cases of cervical cancer. Women with cervical cancer are treated primarily by surgery or chemoradiotherapy; a small number require both modalities. For early-stage small-volume disease, surgery or radiotherapy alone appears to be equally effective (Eifel 1991); however, surgery may be more beneficial in younger women, in that ovaries can be preserved and vaginal atrophy and stenosis avoided.
Cancer of the vulva is rare; when coupled with cancer of the vagina, it accounts for less than 1% of all cancer cases and 8% of gynaecological cancers diagnosed in the UK. In 2008, 1157 new cases of vulval cancer were diagnosed in the UK, equating to a European age-standardised incidence rate of 2.5 per 100,000 female population (Cancer Registration in NI 2011;Cancer Registrations in Wales 2010; ISD Scotland 2011; Office for National Statistics 2011). An estimated 27,000 women worldwide are diagnosed with vulval cancer each year (Sankaranarayanan 2006), and it has been estimated that the lifetime risk of developing vulval cancer is around 1 in 293 for women in the UK. The management of women with vulval cancer usually involves surgery initially, which is necessary to stage and control the disease and to prevent local recurrence. Radiotherapy may be given as a primary form of treatment in those women with larger, more advanced lesions involving bladder or rectum, or who are considered unsuitable for surgery. It may also be used as an adjunct to surgery in patients who have inadequate surgical resection margins or lymph node involvement.
The biology of recurrent ovarian cancer differs from that of other gynaecological cancers; its management is therefore the subject of a separate review (Al Rawahi 2010).
Description of the intervention
Unfortunately, given the nature of the disease, in most patients with cancer, the condition will recur or progress at some point in their lives. Cancer recurrence is defined as the return of cancer after treatment and after a period of time during which the cancer is undetectable. Progression is seen when cancer metastasises or worsens. The difference between recurrence and progression is not always clear, and the definition of recurrence includes no standard period of time; however, most would consider a cancer to be recurrent when it appears after 12 months of a disease-free state (American Cancer Society 2011).
Although the management of early-stage cancers is relatively straightforward, with lower associated morbidity and mortality, the surgical management of advanced and recurrent malignancies is significantly more complicated, often requiring very extensive procedures. The mainstay for treatment success in terms of locoregional control and long-term survival is resection of the pelvic tumour with clear margins (Höckel 2006).
Pelvic exenterative surgery involves removal of part or all of the pelvic organs, namely, the rectum (with or without the sigmoid colon), bladder, reproductive organs (including vagina and vulva), pelvic peritoneum, and sometimes the perineum, with reconstruction. Since it was first described by Brunschwig in 1948, the development of newer techniques of resection and pelvic reconstruction over the past few decades has led to a considerable reduction in the frequency of complications and perioperative mortality (Brunschwig 1948; Höckel 2006; Höckel 2008; Lawhead 1989; Shingleton 1989; Stanhope 1990; Symmonds 1975). The reconstruction of pelvic floor defects after extensive surgical resection of genital malignancies presents multiple challenges. The pelvic dead space predisposes patients to problems with ileus, haematomas, abscesses, and fistulae. The reconstruction of pelvic wall defects with omental flaps, bowel anastomoses, and the creation of neo-vaginas has decreased some of these complications (Schmidt 2012; Soper 1989; Buchsbaum 1973). In recent years, surgeons undertaking exenterative surgery aim to create neo-vaginas from bowel segments, to achieve primary anastomosis of the rectosigmoid colon, and to create a continent bladder where possible, giving patients a much improved quality of life (Schmidt 2012).
The most common indication for exenteration is cervical carcinoma that is persistent or has recurred after radiotherapy (Höckel 2006). The intent of exenterative surgery should be resection of all tumour with the aim of cure. It is a radical, often mutilating procedure associated with significant post-operative morbidity, and is a major undertaking for both patient and surgeon, but it may be the only curative intervention in women with recurrent malignant disease. The reduction in mortality over the past few decades is the result of improvements in surgical and anaesthetic techniques, the use of prophylactic antibiotics, thromboprophylaxis, and intensive care monitoring. Despite this, peri-operative and post-operative morbidity rates continue to remain significant, albeit on the decrease. As a result of various improvements in peri-operative management, treatment-related mortality has dropped to less than 10% and 5-year survival has increased to 40% to 50% for patients with advanced pelvic malignant disease that was otherwise untreatable (Höckel 2006). In locally advanced and recurrent pelvic malignancies, adequate clearance often cannot be achieved without resection of other pelvic viscera.
Women with progressive disease are likely to have tumours that differ biologically from tumours found in those with recurrent disease, have a poorer prognosis, and are unlikely to be offered exenterative surgery as part of their treatment. We have therefore limited this review to discussion of women with recurrent disease regardless of the type of primary treatment received.
Why it is important to do this review
Exenterative surgery in the management of persistent or recurrent cancer after initial treatment is difficult and is associated with significant peri-operative morbidity and mortality. However, it provides these women with a chance of cure that otherwise may not be possible. The aim of this review is to examine the available evidence for exenterative surgery in the management of women with recurrent gynaecological cancer. To our knowledge, no previous systematic reviews have addressed this subject.
To evaluate the effectiveness and safety of exenterative surgery for women with recurrent gynaecological cancer, excluding recurrent ovarian cancer.
Criteria for considering studies for this review
Types of studies
For completeness, we will search for relevant randomised controlled trials (RCTs) and quasi-randomised trials, but after consulting experts in the field, we do not expect to find such trials. So the following types of non-randomised studies with concurrent comparison groups will also be included:
Non-randomised trials, prospective and retrospective cohort studies, and case series of 30 or more patients.
Case-control studies and case series of fewer than 30 patients will be excluded.
To minimise the effects of selection bias (systematic differences between baseline characteristics of the groups that are compared), we will include only studies that provided statistical adjustment for baseline case mix using multi-variable analyses (e.g. adjusting for age, stage, performance status, grade) if any constraints were placed on treatment allocation (e.g. women with poor performance status would not be given surgery), or if treatment allocation was based on clinician preference.
Types of participants
Adult women (aged 18 years and older) diagnosed with a recurrent gynaecological cancer. Women with recurrent ovarian cancer will be excluded because treatments for these patients have been addressed in a separate Cochrane Review.
Types of interventions
Intervention: Exenterative surgery. This may be anterior (removal of the bladder and formation of urinary diversion; usually an ileal conduit with or without hysterectomy, with or without resection of the vagina and perineum), posterior (removal of the rectosigmoid colon with formation of an end colostomy with or without hysterectomy), or total. Some more extensive recurrences will also require resection of the vulva. We will also include exenterative procedures for recurrent (or progressive) vulval cancers.
Comparison: Chemotherapy, radiotherapy, chemoradiotherapy, or expectant management.
Types of outcome measures
Overall survival: survival until death from all causes.
- Progression-free survival.
- Disease-specific survival.
- Time to relapse/progression.
- Resection margin status.
- Death within 30 days of intervention.
- Adverse events classified according to CTCAE 2006:
- Direct surgical morbidity (e.g. vascular injury; injury to bladder, ureter, small bowel, or colon; presence and complications of adhesions; febrile morbidity) intestinal obstruction, anastomotic leak, haematoma, local infection, blood loss.
- Surgically related systemic morbidity (e.g. chest/wound/urine infection), thromboembolic events (deep vein thrombosis and pulmonary embolism), cardiac events (cardiac ischaemia, myocardial infarction, and cardiac failure), cerebrovascular accident, transfusion reaction, pulmonary oedema.
- Recovery: delayed discharge, unscheduled re-admission.
- Abandoned procedure.
- Quality of life (QoL) measured using a scale that has been validated through reporting of norms in a peer-reviewed publication.
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 Review Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from 1966 to present day.
The Medline search strategy is presented in Appendix 1.
All relevant articles found will be identified on PubMed, and through use of the 'related articles' feature, further searches will be carried out for newly published articles.
Searching other resources
Unpublished and Grey literature
A Google search will be conducted for Internet-based resources and open-access publications. Metaregister (http://www.controlled-trials.com/rct), Physicians Data Query (http://www.nci.nih.gov), http://www.clinicaltrials.gov), and http://www.cancer.gov/clinicaltrials will be searched for ongoing trials. If ongoing trials that have not been published are identified through these searches, the principal investigators will be asked for relevant data. The major co-operative trials groups active in this area will likewise be approached.
Conference proceedings and abstracts will be searched through ZETOC (http://zetoc.mimas.ac.uk) and WorldCat Dissertations.
We will also contact experts in the field, including NIck Spirtos, Denis Chi, Charlie Chan, Achim Schneider, Christardt Kohler, Michael Hockel, John Shepherd, William Cliby, and Neville Hacker.
The citation lists of included studies, key textbooks, and previous systematic reviews will be handsearched.
Reports of conferences will be handsearched in the following sources:
- Gynecologic Oncology (Annual Meeting of American Society of Gynecologic Oncologists).
- International Journal of Gynecological Cancer (Annual Meeting of International Gynecologic Cancer Society).
- British Journal of Cancer.
- British Cancer Research Meeting.
- Annual Meeting of European Society of Medical Oncology (ESMO).
- Annual Meeting of American Society of Clinical Oncology (ASCO).
Data collection and analysis
Selection of studies
All titles and abstracts retrieved by electronic searching will be downloaded to a reference management database, Endnote. Duplicates will be removed and remaining references will be examined independently by two review authors (CA, AB). Studies that clearly do not meet the inclusion criteria will be excluded, and copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two review authors (CA, AB). Disagreements will be resolved by discussion between the two review authors and, if no consensus is reached, by a third review author (RN). Reasons for exclusion will be documented.
Data extraction and management
For included studies, data were abstracted as recommended in Chapter 7 of the Cochrane Handbook 2008. Data on the following were included:
- Author, year of publication, and journal citation (including language).
- Inclusion and exclusion criteria.
- Study design, methodology.
- Study population:
- Total number enrolled.
- Patient characteristics.
- Previous treatment.
- Gynaecological cancer details at diagnosis:
- Type of cancer.
- Original treatment modality.
- Intervention (exenterative surgery) details:
- Single or multiple centres.
- Cystectomy and formation of urinary diversion.
- Resection of the vagina +/- perineum.
- Rectosigmoid colectomy with formation of an end colostomy.
- Duration of procedure.
- Type of surgeon (gynaecological oncologist, urologist, colorectal surgeon, surgeon performing joint procedures).
- Comparison details:
- Type of treatment or expectant management.
- Dose (If appropriate).
- Combination (If appropriate).
- Risk of bias in study (see below).
- Duration of follow-up.
- Outcomes – Overall and progression-free survival, QoL, and severe 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, missing participants.
Data on outcomes were extracted as below:
- For time to event (overall survival (OS) and progression-free survival (PFS)) 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 patients in each treatment arm who experience the outcome of interest and the number of patients assessed at endpoint, to estimate a risk ratio (RR).
- For continuous outcomes (e.g. QoL), 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, to estimate the mean difference (if trials measured outcomes on the same scale) or standardised mean differences (if trials measured outcomes on different scales) between treatment arms and standard error.
Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which participants are analysed in groups to which they were assigned.
The time points at which outcomes were collected and reported will be noted.
Data will be abstracted independently by two reviewers (CA, AB) onto a data abstraction form specially designed for the review. Differences between reviewers will be resolved by discussion or by appeal to a third reviewer (RN).
Assessment of risk of bias in included studies
The risk of bias in included RCTs will be assessed 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 healthcare providers to surgical intervention).
- incomplete outcome data:
- We will record the proportion 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:
- 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 are different between treatment arms,
- Unclear if loss to follow-up is not reported.
- selective reporting of outcomes.
- other possible sources of bias.
As we included observational studies, we assessed risk of bias in accordance with the following additional criteria.
- Were relevant details of criteria for assignment of patients to treatments provided?
- Low risk of bias (e.g. yes).
- High risk of bias (e.g. no).
- Unclear risk of bias.
- Was the group of women who received the experimental intervention (exenterative surgery) representative?
- Low risk of bias (e.g. yes, as they were representative of women with gynaecological cancer).
- High risk of bias (e.g. no, as group of patients was selected).
- Unclear risk of bias (e.g. selection of group was not described).
- Was the group of women who received the comparison intervention (e.g. chemotherapy) representative?
- Low risk of bias (e.g. yes, as drawn from the same population as the experimental cohort).
- High risk of bias (e.g. no, as drawn from a different source).
- Unclear risk of bias (e.g. selection of group was not described).
We will assess cohort comparability on the basis of study design or analysis of cohort differences.
- Were there no differences between the two groups or were differences controlled for, in particular with reference to age, FIGO (International Federation of Gynecology and Obstetrics) stage, histological cell type, and differentiation?
- Low risk of bias, if age and at least two other of these characteristics were reported, and any reported differences were controlled for.
- High risk of bias, if the two groups differed, and differences were not controlled for.
- Unclear risk of bias, if fewer than three of these characteristics were reported, even if there were no other differences between the groups, and other characteristics were controlled for.
The risk of bias tool will be applied independently by two review authors (CA, AB) and differences will be resolved by discussion or by appeal to a third reviewer (RN). Results will be summarised in both a risk of bias graph and a risk of bias summary. Results of meta-analyses will be interpreted 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), if possible.
- For dichotomous outcomes, we will use the relative ratio (RR).
- 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 if 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
Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials that 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 (Subgroup analysis and investigation of heterogeneity). If evidence of substantial heterogeneity is found, the possible reasons for this will be investigated and reported.
Assessment of reporting biases
Funnel plots corresponding to meta-analysis of the primary outcome will be examined to assess the potential for small study effects such as publication bias.
If sufficient clinically similar studies are available, their results will be pooled in meta-analyses.
- For time-to-event data, HRs will be pooled using the generic inverse variance facility of RevMan 5.
- For any dichotomous outcomes, the RR will be calculated for each study, and these will then be pooled.
- For continuous outcomes, mean differences between treatment arms at the end of follow-up will be pooled if all studies measured the outcome on the same scale; otherwise standardised mean differences will be pooled.
Random-effects models with inverse variance weighting will be used for all meta-analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
We will subgroup by tumour site and type of primary treatment (chemotherapy, radiotherapy, surgery, or any combination).
Sensitivity analyses will be performed excluding studies at high risk of bias.
We thank Jo Morrison for her clinical input. We thank 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 Pelvic Exenteration/
3 exp Colectomy/
4 (exenterat* or eviscerat* or evidement or cystectomy or colectomy).mp.
5 1 or 2 or 3 or 4
6 exp Genital Neoplasms, Female/
7 ((gynecolog* or gynaecolog* or uter* or cervi* or endometri* or vulva* or vagina*) adj5 (cancer* or tumor* or tumour* or malignan* or neoplas* or carcinoma* or adenocarcinoma*)).mp.
8 6 or 7
9 5 and 8
10 randomized controlled trial.pt.
11 controlled clinical trial.pt.
14 clinical trials as topic.sh.
17 exp Cohort Studies/
18 (cohort* or prospective* or retrospective*).mp.
19 (case* and series).mp.
20 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21 9 and 20
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier, pt=publication type, sh=subject heading, ab=abstract, ti=title
Contributions of authors
CA drafted the clinical sections of the protocol, with input from RN, DB, and CP; AB drafted the methodological sections of the protocol. All authors approved 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