Description of the condition
Cervical cancer is the second most common gynaecological cancer and also the second most common cause of gynaecological cancer deaths in women after breast cancer, with an estimated 529,400 new cases and 274,900 deaths in 2008 (Ferlay 2008). It is therefore a persistent, major, global public health problem. The majority of cervical cancer cases (85% or 452,900 cases) and deaths (88% or 241,700) occurred in developing countries. A woman's cumulative risk of developing cervical cancer by age 74 is 0.9% in developed countries compared to 1.9% in developing countries (Ferlay 2008). Aside from a higher incidence of cervical cancer in developing countries, the patients in these areas also have a higher proportion of locally-advanced stages, including stage IB2 or IIB-IVA of the International Federation of Gynecology and Obstetrics (FIGO) staging classification or advanced stage IVB cancers (Moore 2010). This is partly due to lack of co-ordinated screening programmes and/or lack of access to radiotherapy, leading to a poorer overall survival. Thus, seeking further means of improving treatment outcomes for advanced or locally-advanced cervical cancer (LACC) is urgent.
Description of the intervention
Concurrent chemoradiation therapy (CCRT), which treats localised disease in the pelvis, is a standard treatment for LACC and has improved survival outcomes compared to radiation therapy alone (Green 2005). Chemotherapy given with radiation therapy serves as a radio-sensitiser, which enhances the activity of radiation, and as a direct cytotoxin to local tumour cells and subclinical distant metastases or spreading of diseases beyond the radiation area (Rose 2002). Despite an improved survival rate with CCRT against radiation therapy alone, local and distant failures (17% and 18%, respectively) of LACC are encountered (Eifel 2004), with overall survival rates ranging from 60 to 65% (Cochrane Meta-Analysis Collaboration 2008). One method of improving treatment outcomes among these patients is to give additional chemotherapy after the main treatment of radiation therapy (formerly) or CCRT (currently). Additional chemotherapy after the standard treatment has been reported in many studies and some practitioners have referred to it as 'consolidation chemotherapy' (Vrdoljak 2006; Choi 2007; Zhang 2010) while others refer to it as 'adjuvant chemotherapy' (ACT) (Lorvidhaya 2003; Dueñas-González 2011; Tang 2012).
How the intervention might work
The objective of additional chemotherapy after completion of radiation therapy or CCRT is to consolidate the effect of chemotherapy given with radiation therapy, to attempt to eradicate the tumour cells outside of the radiation field. The role of consolidation chemotherapy or ACT has been explored in several studies or trials involving LACC (Wong 1999; Lorvidhaya 2003; Vrdoljak 2006; Choi 2007; Domingo 2009; Choi 2010; Zhang 2010; Dueñas-González 2011; Tang 2012). All single arm phase II studies, which evaluated the role of ACT in LACC, had a higher response rate than those obtained after completion of CCRT alone. The overall survival rates of over 80 to 90% achieved by CCRT followed by ACT (Vrdoljak 2006; Choi 2007; Domingo 2009; Zhang 2010) were also higher than the 60 to 65% obtained by CCRT alone (Cochrane Meta-Analysis Collaboration 2008). Most of the randomised trials identified indicated that there was a survival advantage from ACT given after CCRT (Wong 1999; Dueñas-González 2011; Tang 2012), except in one trial (Lorvidhaya 2003).
Why it is important to do this review
Concurrent chemoradiation therapy (CCRT) is the current standard treatment for locally-advanced cervical cancer (LACC); however, it can only yield a 60 to 65% survival rate. Additional chemotherapy after CCRT is therefore one possible way to extend the survival of LACC patients, because it may further reduce or eradicate any residual disease, including occult disease outside the pelvic radiation field. Although the survival benefit from additional or ACT after CCRT has been demonstrated in some studies, this finding has not been consistently demonstrated. Furthermore, each study has specific characteristics vis-à-vis the population included and the different types of chemotherapy regimen given especially between the two study arms in the same trial. Without a clear benefit of ACT after CCRT, there has been no definite recommendation or clinical practice guideline for its use. Since chemotherapy is expensive and can cause toxicities, any potential survival advantages must outweigh these disadvantages.
Since evidence regarding the benefit of ACT after a standard CCRT for LACC is inconsistent, a systematic review and meta-analysis to evaluate the efficacy of this treatment option is warranted.
To assess whether ACT given after CCRT improves survival of LACC patients compared to CCRT alone. Adverse effects of ACT will also be evaluated.
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 interventions
- Intervention: ACT after CCRT
- Comparator: CCRT, then placebo or no further treatment
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:
- toxicity during CCRT;
- toxicity during ACT;
- other side-effects not categorised above.
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:
- Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register;
- Cochrane Central Register of Controlled Trials (CENTRAL);
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:
- metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/);
- Physicians Data Query (http://www.cancer.gov/cancertopics/pdq/cancerdatabase);
- ClinicalTrials.gov (http://clinicaltrials.gov/);
- National Cancer Institute (http://www.cancer.gov/clinicaltrials);
- World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/).
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
- 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.
We thank Jo Morrison for clinical advice, Jane Hayes, for designing the search strategy, Gail Quinn and Clare Jess for their contribution to the editorial process and Bryan and Janice Hamman for assistance with English-language presentation.
Appendix 1. MEDLINE search strategy
1. Uterine Cervical Neoplasms/
2. (cervi* adj5 (cancer* or neoplas* or carcinoma* or tumor* or tumour* or malignan*)).mp.
3. 1 or 2
5. exp Radiotherapy/
6. exp Chemoradiotherapy/
7. (radiotherap* or radiat* or irradiat* or chemoradi* or radiochemo*).mp.
8. 4 or 5 or 6 or 7
9. drug therapy.fs.
10. exp Antineoplastic Agents/
11. Antineoplastic Combined Chemotherapy Protocols/
12. Chemotherapy, Adjuvant/
14. 9 or 10 or 11 or 12 or 13
15. 3 and 8 and 14
16. randomized controlled trial.pt.
17. controlled clinical trial.pt.
20. clinical trials as topic.sh.
23. 16 or 17 or 18 or 19 or 20 or 21 or 22
24. 15 and 23
25. exp animals/ not humans.sh.
26. 24 not 25
key: mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier, pt=publication type, ab=abstract, ti=title, sh=subject heading, fs=floating subheading, exp=exploded term
Appendix 2. The Cochrane Collaboration's tool for assessing risk of bias in included studies
Random sequence generation
- Low risk of bias e.g. participants assigned to treatments on basis of a computer-generated random sequence or a table of random numbers
- High risk of bias e.g. participants assigned to treatments on basis of date of birth, clinic id-number or surname, or no attempt to randomise participants
- Unclear risk of bias e.g. not reported, information not available
- Low risk of bias e.g. where the allocation sequence could not be foretold
- High risk of bias e.g. allocation sequence could be foretold by patients, investigators or treatment providers
- Unclear risk of bias e.g. not reported.
Blinding of participants and personnel (not applicable)
Blinding of outcomes assessors
- Low risk of bias if outcome assessors were adequately blinded
- High risk of bias if outcome assessors were not blinded to the intervention that the participant received
- Unclear risk of bias if this was not reported or unclear
Incomplete outcome data
We will record the proportion of participants whose outcomes were not reported at the end of the study. We will code a satisfactory level of loss to follow-up for each outcome as:
- Low risk of bias, if fewer than 20% of patients were lost to follow-up and reasons for loss to follow-up were similar in both treatment arms
- High risk of bias, if more than 20% of patients were lost to follow-up or reasons for loss to follow-up differed between treatment arms
- Unclear risk of bias, if loss to follow-up was not reported
Selective reporting of outcomes
- Low risk of bias e.g. review reports all outcomes specified in the protocol
- High risk of bias e.g. it is suspected that outcomes have been selectively reported.
- Unclear risk of bias e.g. it is unclear whether outcomes had been selectively reported
- Low risk of bias - if no source of bias is suspected and the trial appears to be methodologically sound
- High risk of bias - if the trial is suspected to an additional bias you suspect
- Unclear risk of bias - if you are uncertain whether an additional bias may have been present
Adopted from Higgins 2011
Contributions of authors
All authors contributed to the development of this protocol.
Declarations of interest
Sources of support
- Faculty of Medicine Vajira Hospital, University of Bangkok Metropolis, Thailand.
- Faculty of Medicine, Khon Kaen University, Thailand.
- Faculty of Public Health, Khon Kaen University, Thailand.
- Thailand Research Fund (Senior Research Scholar), Thailand.
- Thai Cochrane Network, Thailand.