Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary aim is to assess the role of neoadjuvant chemotherapy in women with early or locally advanced cervical cancer compared with surgery. A secondary aim is to assess whether any pre‐defined trial group benefits more or less from neoadjuvant chemotherapy.
Background
Globally, cervical cancer is the second most common female cancer with almost 500,000 new cases diagnosed every year (Parkin 2005; WHO 2006). The majority of these cases (about 80%) occur in less developed countries, where it is often the most common female cancer (Parkin 2005). There has been a decline in cases seen in North America and Europe (Sasieni 1995), mainly as a result of successful screening programs (Devesa 1995) but there are still almost 300,000 deaths from this disease recorded annually (Parkin 2005).
Description of the condition
Approximately 80% of cervical cancer cases are squamous cell carcinomas, about 15% are classified as adenocarcinomas and the remainder are adenosquamous carcinomas (Witteveen 2002). The main underlying cause of squamous cervical cancer is infection with human papillomavirus (HPV), a common sexually transmitted virus. There are several types of this virus and those most associated with a risk of cervical cancer are types 16 and 18. Persistent infection can lead to lesions developing into abnormal tissue known as cervical intra‐epithelial neoplasia (CIN), which over a period of 10 to 20 years can become invasive cervical cancer. Spread of the disease from the cervix can be in all directions, down to the vagina, up into the uterus, backwards into the rectum, forwards into the bladder and sideways into the tissues supporting the uterus in the pelvis. The rate of cure for this type of cancer is directly related to the stage at diagnosis so screening and early detection play an important role in the management of this disease.
Description of the intervention
Neoadjuvant chemotherapy involves giving chemotherapy prior to surgery.
How the intervention might work
Surgery has already been shown to be an effective treatment for cervical cancer. Chemotherapeutic tumour reduction may improve resectability rates as well as helping to reduce surgical morbidity by allowing for more conservative surgery (Sardi 1990). The systemic action of chemotherapy drugs may also act by helping to eliminate microscopic metastatic disease (Thigpen 1981).
Why it is important to do this review
Historically the standard treatment for patients with earlier stage (IB1‐IIA) cervical cancers has been radical surgery or radical radiotherapy. Both of these treatments have been shown to be equally effective in this type of cancer, each having 5 year survival rates of between 80 to 90% (Benedet 1998; Landoni 1997).
Until 1983, cervical cancer was thought to be resistant to chemotherapy but the discovery that these tumours were in fact sensitive to chemotherapy (Friedlander 1983) led to the initiation of studies looking at adding chemotherapy to radiotherapy and surgery. Since an NCI alert in 1999 (NCI 1999), chemoradiotherapy has become standard care for women with locally advanced cervical cancer. However, surgery is still a valid treatment option, especially in earlier stage disease.
There are also several possible advantages to giving neoadjuvant chemotherapy prior to surgery, especially in light of the advances in surgical techniques in recent years. As well as the potential for reducing tumour volume, increasing resectability and helping to control micrometastatic disease, neoadjuvant chemotherapy may also provide a potentially viable alternative when there is no access to radiotherapy or if there are unavoidable delays in delivering radiotherapeutic treatment.
The roles of neoadjuvant chemotherapy followed by either surgery or radiotherapy versus radiotherapy alone have already been assessed in a previous review (NACCCMA 2003). The authors found a benefit of giving neoadjuvant chemotherapy prior to surgery when compared with radical radiotherapy. However, the best way to assess what chemotherapy adds to surgery is to compare it with surgery alone. Therefore, this review aims to compare the effects of neoadjuvant chemotherapy plus surgery versus surgery.
Objectives
The primary aim is to assess the role of neoadjuvant chemotherapy in women with early or locally advanced cervical cancer compared with surgery. A secondary aim is to assess whether any pre‐defined trial group benefits more or less from neoadjuvant chemotherapy.
Methods
Criteria for considering studies for this review
Types of studies
Closed randomised controlled trials (RCTs) with patient accrual from 1980 onwards, comparing neoadjuvant chemotherapy plus surgery versus surgery.
Types of participants
Only RCTs that have aimed to recruit women (of any age) with early or locally advanced cervical cancer who have not undergone any prior treatment likely to interfere with this comparison will be included.
Types of interventions
Neoadjuvant chemotherapy followed by surgery versus surgery. Trials that used adjuvant radiotherapy after surgery were allowed provided this was given in both arms.
Types of outcome measures
Primary outcomes
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Overall survival (OS)
Secondary outcomes
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Overall disease‐free survival (DFS)
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Local recurrence
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Distant recurrence
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Rates of resection
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Surgical morbidity
Search methods for identification of studies
Searches will be conducted to identify all published and unpublished RCTs comparing neoadjuvant chemotherapy with surgery alone in early and locally advanced cervical cancer. Systematic searches of a number of trial sources will be undertaken with no restriction on the language of publication. Non‐English abstracts and papers will be translated as necessary to assess their potential eligibility for inclusion in the review.
Search strategies will be tailored to individual databases to maximise the potential for identifying relevant trials.
Electronic searches
The following databases will be searched electronically: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1980 to present), (1980 to present), LILACS (1982 to present), PDQ (1982 to present), American Society of Clinical Oncology (ASCO) annual meeting abstracts (1995 to present), International Journal of Gynecological Cancer Society (IGCS) abstracts (2000‐present) and European Society of Gynaecological Oncology (ESGO) abstracts (2000 to present).
MEDLINE will be searched using the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (sensitivity‐maximizing version, 2008) together with MeSH and free text terms specific to the review Appendix 1. Search strategies are also shown for CENTRAL Appendix 2 and LILACS (Manriquez 2008) Appendix 3 databases.
ASCO abstracts will be searched using cervi$ as a keyword and PDQ will be searched using cervical cancer, surgery, and chemotherapy as keywords.
Searching other resources
Reference lists of relevant publications and reviews will also be handsearched to identify further trial reports.
Data collection and analysis
Selection of studies
Full papers will be obtained for all potentially relevant abstracts and these will be assessed by two independent review authors. Those not meeting the inclusion criteria will be excluded from the review at this stage. All titles and abstracts identified by electronic searches and by hand searching will be downloaded to a reference management database and any duplicates removed. Efforts will also be made to identify multiple reports of the same study to avoid duplication.
Data extraction and management
Data on patient characteristics, interventions and outcomes will be extracted onto pre‐designed forms and independently checked and assessed by two review authors with any disagreements resolved by consensus with a third review author if necessary. Further information may be sought from publication authors if papers do not contain enough information to allow trial data to be included in the review.
Assessment of risk of bias in included studies
Various aspects of the methodological quality of included studies will be independently assessed by two review authors, using the risk of bias tool (Table 1, taken from the Cochrane Handbook (Higgins 2008)) and any discrepancies will be resolved by consensus with a third review author if necessary.
| Sequence generation. | Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. | Was the allocation sequence adequately generated? |
| Allocation concealment. | Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment. | Was allocation adequately concealed? |
| Blinding of participants, personnel and outcome assessorsAssessments should be made for each main outcome (or class of outcomes). | Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective. | Was knowledge of the allocated intervention adequately prevented during the study? |
| Incomplete outcome dataAssessments should be made for each main outcome (or class of outcomes). | Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re‐inclusions in analyses performed by the review authors. | Were incomplete outcome data adequately addressed? |
| Selective outcome reporting. | State how the possibility of selective outcome reporting was examined by the review authors, and what was found. | Are reports of the study free of suggestion of selective outcome reporting? |
| Other sources of bias. | State any important concerns about bias not addressed in the other domains in the tool. If particular questions/entries were pre‐specified in the review’s protocol, responses should be provided for each question/entry. | Was the study apparently free of other problems that could put it at a high risk of bias? |
Measures of treatment effect
For meta‐analyses of time‐to‐event outcomes such as OS and overall DFS, the most appropriate statistic is the hazard ratio (HR). Where available the HR and associated statistics will be extracted directly from the trial report. If the HR is not provided in the trial report then it will be estimated indirectly from Kaplan Meier curves or other summary statistics, using published methods (Parmar 1998; Tierney 2007; Williamson 2002). Where possible, a number of methods will be used to indirectly estimate the HR to check its reliability. For dichotomous outcomes such, as resection rates, an odds ratio (OR) of the rate of recurrence will be calculated.
Unit of analysis issues
It is envisaged that all included trials will have randomised individual patients to either the treatment or control arms of the study. Therefore, the unit of analysis will be the patient.
Dealing with missing data
Where the publication does not provide enough data, and this would preclude reliable estimation of treatment effect, we will consider contacting the trial authors for further information. If there is insufficient data available for any particular outcome this will then be described qualitatively rather than analysed quantitatively.
Assessment of heterogeneity
Heterogeneity will be assessed using the I2 statistic, Chi2 and degrees of freedom (df). Heterogeneity will be considered to be substantial in cases where the value of I2 is greater than 50% and when Chi2 greater than degrees of freedom and p less than 0.1. Reasons for any substantial heterogeneity detected will be explored using trial subgroup and sensitivity analyses.
Assessment of reporting biases
If sufficient trials exist, formal methods (as described by Egger et al in the Cochrane Handbook) will be used to investigate the presence of reporting bias.
Data synthesis
The HRs and ORs from each of the individual eligible trials will be combined in a meta‐analysis to give a pooled HR and OR, using the fixed effects model (FEM). A random effects model (REM) will also be used to test the robustness of the results to the choice of model.
Subgroup analysis and investigation of heterogeneity
If sufficient data are available, analyses will be carried out in pre‐specified trial subgroups categorised by chemotherapy dose and chemotherapy cycle length to see if there is any difference in treatment effect. Further subgroup analysis will consider any differences between the trials categorised by the cervical cancer stage included.
Sensitivity analysis
If heterogeneity is detected and cannot be explained by subgroup analyses then sensitivity analyses may be conducted.
| Sequence generation. | Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. | Was the allocation sequence adequately generated? |
| Allocation concealment. | Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment. | Was allocation adequately concealed? |
| Blinding of participants, personnel and outcome assessorsAssessments should be made for each main outcome (or class of outcomes). | Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective. | Was knowledge of the allocated intervention adequately prevented during the study? |
| Incomplete outcome dataAssessments should be made for each main outcome (or class of outcomes). | Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re‐inclusions in analyses performed by the review authors. | Were incomplete outcome data adequately addressed? |
| Selective outcome reporting. | State how the possibility of selective outcome reporting was examined by the review authors, and what was found. | Are reports of the study free of suggestion of selective outcome reporting? |
| Other sources of bias. | State any important concerns about bias not addressed in the other domains in the tool. If particular questions/entries were pre‐specified in the review’s protocol, responses should be provided for each question/entry. | Was the study apparently free of other problems that could put it at a high risk of bias? |
