Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Women aged ≥18 years old who were diagnosed with: cervical cancer, FIGO stage IB2 to IVA, and a histopathology of squamous cell carcinoma, adenosquamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma. All patients must have had CCRT before receiving ACT.
Types of outcome measures
Overall survival, analysed from the date of diagnosis until death or the patient's last visit
Progression-free survival analysed from the date of diagnosis until an appearance of new lesion during treatment or a greater than 25% increase in size of local tumour
Response rates after completion of CCRT, and after adjuvant ACT
Quality of life, measured using a scale that has been validated through reporting of norms in a peer-reviewed publication
Adverse events, classified according to CTCAE 2006, for example:
Grades of toxicity will be grouped as:
haematological (leucopenia, anaemia, thrombocytopenia, neutropenia, haemorrhage);
gastrointestinal (nausea, vomiting, anorexia, diarrhoea, liver, proctitis);
skin (stomatitis, mucositis, alopecia, allergy);
neurological (peripheral and central);
Search methods for identification of studies
We will search for papers in all languages and have them translated as necessary.
We will search the following electronic databases:
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 on PubMed and using the 'related articles' feature and perform further searches for newly published articles.
Searching other resources
Unpublished and grey literature
We will search the following for ongoing trials:
If ongoing trials that have not been published are identified through these searches, we will approach the principal investigators, and major co-operative groups active in this area, to ask for relevant data.
Electronic databases such as Zetoc (http://zetoc.mimas.ac.uk/) and OCLC WorldCat Dissertations and Theses (WorldCatDissertations) (http://www.oclc.org/support/documentation/firstsearch/databases/dbdetails/details/worldcatdissertations.htm) will be searched for the conference proceedings and abstracts.
Handsearch the citation lists of included studies, key textbooks, and contact experts in the field to identify further reports of trials. Also hand-search for any previous systematic reviews and the reports of conferences in the following sources:
Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologist);
International Journal of Gynecological Cancer (Biannual Meeting of the International Gynecologic Cancer Society and biannual Meeting of the European Society of Gynaecologic Oncology);
British Journal of Cancer;
British Cancer Research Meeting;
Annual Meeting of European Society of Medical Oncology;
Annual Meeting of the American Society of Clinical Oncology.
Data collection and analysis
Selection of studies
Two authors (ST, KK) will independently examine search results obtained and exclude the records which clearly do not meet the inclusion criteria. We will obtain copies of the full text of potentially relevant references. The two authors (ST, KK) will independently assess the eligibility of the retrieved full-text articles. Disagreements will be resolved by discussion between the two authors and if necessary by consulting a third author (PL). Reasons for exclusion will be documented.
Data extraction and management
Two authors (ST, KK) will extract data independently using a data abstraction form specially designed for the review. The two authors will resolve differences between authors by discussion or by appeal to a third author (PL) if necessary. For included studies, the following data will be extracted:
author, year of publication and journal citation (including language);
inclusion and exclusion criteria;
study design, methodology;
study population (total number enrolled; patient characteristics; age; co-morbidities; other baseline characteristics);
intervention details (CCRT - regimen, dosage, cycles of treatment; radiation therapy - radiation therapy technique (external pelvic radiation therapy, extended field radiation therapy, brachytherapy), radiation machine or instrument (cobalt, linear accelerator), type of brachytherapy (low-dose or high-dose rate), doses; ACT - regimen, dosage, cycles of treatment);
comparison (primary and secondary outcomes between the two arms);
risk of bias in study (Assessment of risk of bias in included studies);
duration of follow-up;
outcomes (outcome definition and unit of measurement (if relevant); for adjusted estimates, we will record variables adjusted for in analyses);
results (number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants).
Results will be extracted as follows:
for time to event data (survival and disease progression), we will extract the log of the hazard ratio and its standard error from trial reports. If these are not reported, we will attempt to estimate them using the methods by Parmar 1998;
for dichotomous outcomes (e.g. adverse events or deaths, if it is 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.
If reported, we will extract both unadjusted and adjusted statistics. Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which participants will be analysed in 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
The risk of bias in included trials will be assessed using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011; Appendix 2):
selection bias (random sequence generation and allocation concealment);
performance bias (not applicable because interventions were aware by the clinicians);
detection bias (blinding of outcome assessment);
attrition bias (rates of incomplete outcome data and trial with ≥20% missing data will be assessed as high risk of bias);
reporting bias (selective reporting of outcomes).
Two authors (ST, KK) will apply the risk of bias tool independently and differences will be resolved by discussion or by appeal to a third author (PL). We will summarise results 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 pool the results from included studies in meta-analysis if there is adequate numbers of clinically similar studies are available. We will use the following measures of the effect of treatment:
for dichotomous outcomes, the risk ratio (RR) and 95% confidence interval (CI) will be calculated for each trial;
for time to event data, hazard ratio (HR) and 95% CI will be calculated for each study;
for continuous outcomes, the mean difference (MD) and 95% CI between the treatments arms at the end of follow-up will be estimated if all trials measured the outcome on the same scale, otherwise standardised mean difference (SMD) and 95% CI will be estimated.
Unit of analysis issues
The following issues may arise:
multiple observations for the same outcome (e.g. response rates measured one month after CCRT and at completion of ACT, measurements of the status of disease in both loco-regional and systemic);
heterogeneity in the randomisation unit(s) will be acknowledged and a subgroup analysis will investigate the effects of the randomisation unit(s).
Dealing with missing data
Missing outcome data for the primary outcome will not be imputed. If data are missing or only imputed data are reported, the lead authors of the trials where data clarification or missing data for the primary outcomes are required will be contacted by email. Where possible, data allowing an intention-to-treat analysis (data of all participants in the groups to which they were originally randomly assigned) will be extracted.
Assessment of heterogeneity
We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage inconsistency between trials which cannot be ascribed to sampling variation (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001)
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 a sufficient number of studies are identified (e.g. more than 10).
If sufficient, clinically similar studies are available we will conduct meta-analyses using the Cochrane Collaboration's statistical software, Review Manager 2012, using a fixed-effect model. If any trials have multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons.
If heterogeneity cannot be ruled out, we will use the random-effects model with inverse variance weighting for all meta-analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
To investigate heterogeneity of the primary outcomes, subgroup analyses will be performed, grouping the trials by:
type of chemotherapeutic regimen (platinum versus non-platinum-based);
stage of disease (stage IB2 to IIB versus stage III to IVA);
radiation therapy technique (external pelvic radiation therapy, radiation machine (cobalt or linear accelerator), brachytherapy, extended field radiation therapy);
histopathology (squamous cell carcinoma versus others).
Factors such as age, stage, type of intervention, length of follow-up and risk of bias status in interpretation of any heterogeneity will be considered.
We will perform sensitivity analysis by excluding studies at high risk of bias.