Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of the different chemotherapy regimens in the treatment of patients who have recurrent or resistant GTN.
Background
Description of the condition
Gestational trophoblastic disease (GTD) encompasses a group of pregnancy related disorders. This includes the pre‐malignant conditions (complete and partial hydatidiform mole) and the malignant conditions of invasive mole, choriocarcinoma and placental site trophoblastic tumour (PSTT). Gestational trophoblastic neoplasia (GTN) or tumour is a term used to describe the latter three malignant conditions.
The incidence of hydatidiform mole (HM) varies between the different parts of the world; in North America and Europe it is approximately one to three per 1000 pregnancies, while it is higher in Asia and Africa (Chan 2009; Palmer 1994; Tham 2003). GTD can affect women at any reproductive age, however the risk is higher in those less than 16 or greater than 45 years of age (Sebire 2002).
Hydatidiform molar pregnancies can be either partial or complete depending on their morphologic, cytogenic and clinical features. Partial hydatidiform moles (PHM) are generally characterised by the presence of fetal or embryonic tissues with limited swelling and trophoblastic hyperplasia. Whereas, complete hydatidiform moles (CHM) show absence of embryonic tissues with extensive swelling and hyperplasia in trophoblastic tissues. Cytogenically, partial moles are characterised by triploid karyotyping (69 chromosomes), while complete moles have a normal number of chromosomes; all of which are, nearly always, of paternal origin (Fisher 2009).
For the majority of patients, GTD resolves spontaneously following one or more uterine evacuations without a need for chemotherapy. However, in approximately 6% to 20% of CHMs and 0.5% to 1% of PHMs the disease persists and chemotherapy is required (Hancock 2006; Seckl 2009). Choriocarcinoma is the most common malignant form of GTN with PSTT being much less common. They all may follow any type of pregnancy and commonly require chemotherapy (El‐Helw 2007).
Historically patients were stratified into different groups using anatomical, clinical and prognostic scoring systems (Bagshawe 1976; Hammond 1973; WHO GTD 1983). Most recently the combined WHO‐FIGO system (Nagan 2002) was adopted in 2002 by the International Society for the Study of Trophoblastic Diseases (ISSTD) (Kohorn 2000; Nagan 2002). The revised FIGO scoring system differs from WHO in that the ABO blood group risk factor is eliminated and the risk factor for liver metastases is upgraded from two, to the highest group, four. A score of six or less is defined as a low risk due to the merging of the old intermediate risk group (scores 5 and 6) into the existing low risk category (score 0 to 4). A score of seven or more is classed as a high‐risk.
Description of the intervention
Low risk GTN
Patients with low risk GTN are usually treated with single‐agent chemotherapy; most commonly, methotrexate with or without folinic acid or dactinomycin (Alazzam 2009). Irrespective of the first‐line regimen, 10% to 30% of these patients develop resistance (Homeseley 1988; Khan 2003; McNeish 2002). The majority of these patients are subsequently treated with second‐line chemotherapy with or without surgery to achieve remission. Several treatment strategies have been described with various success rates and toxicity profiles:
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Single agent pulsed Dactinomycin (Covens 2006)
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EA (etoposide and dactinomycin) (Dobson 2000)
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EMA/CO (etoposide, methotrexate, dactinomycin/cyclophosphamide, vincristine) (McNeish 2002)
High risk GTN
Patients with high risk GTN are at a higher risk of first‐line treatment failure and therefore, are treated with combination chemotherapy regimen; various combinations have been developed with EMA/CO the most widely used, other regimens, such as MEA (methotrexate, dactinomycin, etoposide), have comparable success rates with relatively reduced toxicity (Dobson 2000; McNeish 2002).
In high risk patients 20% to 30% will either develop resistance or relapse after remission and need salvage chemotherapy (McNeish 2002). In general, there is no chemotherapy regimen with a guaranteed outcome. Several salvage regimens have been reported in the literature, often in small series studies (Lurain 2005; Matsui 2005). In the largest series from Charing Cross Hospital, London, UK (Wang 2008), patients resistant to EMA/CO were treated with weekly alternating regime of EMA/EP (where P is cisplatin). Despite the reported cumulative success rate of 75%, this regime resulted in significant myelosuppression and treatment frequently delayed until recovery of blood counts in 85% of patients or dose reduction in 16% (Newlands 2000). In order to minimise the treatment delays, patients frequently required treatment with granulocyte‐colony stimulating factors (G‐CSF) (El‐Helw 2005). More recently, a number of reports suggested that taxane containing regimen, paclitaxel, cisplatin/paclitaxel, etoposide (TP/TE), can be used as a salvage treatment for high risk patients who fail first‐line chemotherapy with comparable success rates to EMA/EP but more crucially with significantly reduced toxicity (Wang 2008).
Why it is important to do this review
The potential for cure is not the sole consideration when treating patients who are resistant or relapsed after first‐line chemotherapy. Eventually almost 98% of patients with low risk disease and 75% of patients with high risk disease will attain cure (McNeish 2002; Khan 2003). Other considerations are of significant importance when choosing second‐line chemotherapy as regimens have significant differences in side effects, cost, route of administration and patients' compliance. The authors are not aware of any other systematic reviews in this field.
Objectives
To assess the efficacy and safety of the different chemotherapy regimens in the treatment of patients who have recurrent or resistant GTN.
Methods
Criteria for considering studies for this review
Types of studies
Only randomised controlled studies (RCTs) for patients with recurrent GTN will be included. Non‐randomised trials and quasi‐RCTs will not be included, however, relevant articles will be included in the discussion section of the review.
Types of participants
Inclusion Criteria:
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Patients diagnosed with GTN who received first‐line chemotherapy and either developed resistance or relapsed after cure (cure is defined as normalisation of bets human chorionic gonadotropin (ßhCG) or reaching undetectable level and remains so).
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A prognostic scoring system was used in stratifying patients prior to first‐line chemotherapy (Bagshawe 1976; Hammond 1973; Nagan 2002).
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Age 16 years and over
Exclusion Criteria:
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Patients who did not have a prognostic score prior to first‐line treatment.
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Patients who received second‐line treatment due to causes other than resistance or relapse (e.g. change due to toxicity).
Types of interventions
Chemotherapy regimens
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Any chemotherapy regimen used for recurrent or resistant GTN (e.g. methotrexate, dactinomycin, fluorouracil, etoposide) in any dose, duration or frequency.
Settings
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Any setting
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Any provider
Types of outcome measures
Primary outcomes
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Cure rate
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Toxicity: grades of toxicity were extracted and grouped according to CTCAE 2009:
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haematological (anaemia, neutropenia, abnormal liver function)
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gastrointestinal (pain, nausea, vomiting)
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genitourinary (vaginal bleeding)
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skin (stomatitis, mucositis, alopecia,allergy)
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neurological (peripheral and central)
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respiratory (pain, shortness of breath, pleural effusion)
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Secondary outcomes
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Mean number of courses (time) to cure.
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Mean number of courses (time) to failure (failure was defined as change in regimen due to drug resistance or toxicity, or surgery for drug resistance).
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Overall survival (OS).
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Quality of life (QoL), measured by a validated scale.
Search methods for identification of studies
Electronic searches
The search will include the Cochrane Gynaecological Cancer Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL, current issue), Ovid MEDLINE (1950 to present day) and EMBASE (1980 to present day).
The MEDLINE search strategy is outlined in Appendix 1. For databases other than MEDLINE, the search strategy will be adapted accordingly.
Searching other resources
The search will include ongoing trials:
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National Research Registry
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National Cancer Institute (http://www.cancer.gov/)
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Metaregister of Controlled Trials (http://www.controlled‐trials.com/mrct/)
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Medical Research Council Clinical Trial Directory (http://www.ctu.mrc.ac.uk/)
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Australian New Zealand Clinical Trial Registry (http://www.anzctr.org.au/)
Hand searching will be carried out for conference proceedings of the:
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International Society for the Study of Trophoblastic Diseases
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International Gynecological Cancer Society
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European Gynaecological Cancer Society
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Society of Gynecologic Oncologist
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American Society of Clinical Oncology
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British Gynaecological Cancer Society
All relevant papers will be reviewed and bibliographies will be searched to identify additional articles. We will also use the 'related articles feature to identify any relevant articles. Expert opinion will be sought to identify relevant but unpublished studies.
Data collection and analysis
Selection of studies
Following electronic and hand literature searches, two review authors (MA, JT) will independently select articles on the basis of title and/or abstract for full text scrutiny. Studies that do not meet the inclusion criteria will be excluded and copies of the full text of relevant references will be obtained. Two review authors (MA, JT) will independently assess each article to determine whether it meets the review eligibility criteria. Each article will be scrutinised for multiple publication from the same data set. Differences will be initially resolved by discussion between the review authors (MA, JT). Failure to resolve the differences would prompt referral to the other review authors (RO, BH and RC) and a majority decision will be taken.
Data extraction and management
Two review authors (MA, JT) will, independently, extract data using a piloted data extraction form. The extracted information from each study include the following characteristics:
Design:
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Description of randomisation, blinding, number of study centres, study duration and number of study withdrawals.
Participants:
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Number, mean age, mean risk score
Intervention:
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Type and dose of intervention
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Dosing and schedule
Outcomes:
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Where possible data will be extracted to allow intention‐to‐treat (ITT) analysis.
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For dichotomous outcomes (e.g. cure, adverse events, and number of patients who relapsed or died), we will abstract information in each treatment arm in order to estimate a risk ratio (RR).
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For continuous outcomes (e.g. QoL measures and duration of treatment) arithmetic mean and standard deviation (SD) of the outcome of interest in each treatment arm will be extracted.
If the data is insufficient or missing from a trial, authors will be contacted for more information. Differences between the review authors will be resolved by discussion. Failure to resolve differences will prompt referral to other review authors and a majority decision will be taken.
Assessment of risk of bias in included studies
The risk of bias tool will be applied independently by two review authors (MA, JT) and differences resolved by discussion or by appeal to a third review author (RC). Results will be presented 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.
Risk of bias in included RCTs will be assessed using the Cochrane Collaboration's tool (Higgins 2009) and the following criteria:
Was the allocation sequence adequately generated?
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Yes e.g. participants assigned to treatments on basis of a computer‐generated random sequence or a table of random numbers
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No e.g. participants assigned to treatments on basis of date of birth, clinic id‐number or surname, or no attempt to randomise participants
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Unclear e.g. not reported, information not available
Was allocation adequately concealed?
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Yes e.g. where the allocation sequence could not be foretold
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No e.g. allocation sequence could be foretold by patients, investigators or treatment providers
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Unclear e.g. not reported
Were patients, treatment providers (note that blinding of patients and treatment providers is usually possible only for pharmacological interventions) and outcome assessors adequately prevented from knowing the allocated interventions during the study?
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Yes
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No
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Unclear
Was loss to follow‐up less than 20% and were the reasons for loss to follow‐up similar in both arms?
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Yes
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No
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Unclear
Are reports of the study free of suggestion of selective outcome reporting?
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Yes e.g. if protocol reports all outcomes specified in the protocol
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No
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Unclear
Was the study apparently free of other problems that could put it at a high risk of bias?
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Yes
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No
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Unclear
Measures of treatment effect
We will use the following measures of the effect of treatment:
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For dichotomous outcomes, we will use the risk ratio (RR).
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For continuous outcome, we will use the mean difference between treatment arms.
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For time to event data, we will use the HR to compare the risk of death in the intervention group with that in the comparison group
Unit of analysis issues
The duration of trials may vary considerably. If the range seems too great to combine all trials into one meta‐analysis, we will divide it into smaller time periods and conduct a separate meta‐analysis for each time period.
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If the outcome of interest is an event that can occur more than once, we will adopt statistical methods for counts data.
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For trials comparing more than two intervention groups, we will assess the relevant intervention group.
Dealing with missing data
For individuals missing data such as drop‐out or loss to follow up, we will use an ITT analysis whenever possible. We will include studies in the review that miss information on outcomes of interest, or miss summary data such as sample sizes, numbers of events, or standard errors. However, we will not consider them in the meta‐analysis. We will contact the chief investigators to request missing data if possible. We will address the potential implications of missing data (e.g. loss to follow up and no outcome obtained, receiving the wrong treatment, lack of compliance, or ineligibility) in the 'Discussion' section.
Assessment of heterogeneity
Heterogeneity between studies will be assessed by visual inspection of forest plots. We will quantify statistical heterogeneity using the I2 statistic, which describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins 2003; Higgins 2009). In cases of substantial heterogeneity we will try to explore their possible sources.
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. When there is evidence of small‐study effects, publication bias will be considered as only one of a number of possible explanations. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random effects model, sensitivity analyses will be performed using fixed effects model.
Data synthesis
If sufficient, clinically similar studies are available their results will be pooled in meta‐analyses.
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For time‐to‐event data, HRs will be pooled using the generic inverse variance facility of RevMan 5.
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For dichotomous outcomes, the RR will be calculated for each trial and these will then be pooled.
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For continuous outcomes, the mean differences between the treatment arms at the end of follow‐up will be pooled if all trials measured the outcome on the same scale, otherwise standardised mean differences will be pooled.
If any trials have multiple treatment groups, the ‘shared’ comparison group will be divided into the number of treatment groups and comparisons between each treatment group and the split comparison group will be treated as independent comparisons.
Random effects models with inverse variance weighting will be used for all meta‐analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
If the data permits; subgroup analysis will be performed, organizing results by 'prognostic scoring system'; low risk versus high risk in which the relapsed tumours in the study population showed to chemotherapy regimen.
Sensitivity analysis
We will evaluate the robustness of the results of meta‐analysis by random‐effects estimates, comparing results of different types of trials, removing trials with low methodological quality, or excluding trials with large effect size.
Several sensitivity analyses will be performed to assess how robust the estimate of the global effect is regarding the:
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Risk of bias (low risk versus high risk)
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Number of patients lost to follow up
