High‐dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents and young adults with first recurrence of Ewing sarcoma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy of HDC with AHCT versus standard‐dose chemotherapy in improving event‐free survival, overall survival, quality adjusted survival and progression‐free survival of children, adolescents and young adults with first recurrence of ES and to determine the toxicity of the treatment.
Background
Description of the condition
Ewing sarcoma (ES) are a group of solid tumours consisting of small blue round cell neoplasms of neuroectodermal origin. ES belongs to the Ewing's family of tumours. The other members of the group include primitive neuroectodermal tumour (PNET), extraosseous Ewing sarcoma (EES) and Askin's tumour (ES of the chest wall). These tumours are thought to arise from the same primordial stem cell. All of these tumours are defined by the presence of EWSR1‐ETS gene re‐arrangements. In 85% of cases, ETS transcription factor fuses with FLI, resulting in theEWS‐FLI fusion protein. This t(11;12)(q24;q12) chromosomal translocation can take place at different intron‐exon sites with more than 18 different translocations described (Delattre 1994; Potratz 2012). ES is the second most common primary bone malignancy in children, accounting for 10% to 15% of all primary bone tumours and approximately 3% of all malignancies in children (Cotterill 2000; Potratz 2012). Most often ES appear in bones; however, extraosseous manifestations may occur. The disease most often occur in children, adolescents and young adults, with an incidence of 4.5 per million a year and with a peak incidence of 11 per million at the age of 12 years (van den Berg 2008).
Much progress has been made in the treatment of ES. With multimodality treatment including multi‐agent chemotherapy, surgery and radiotherapy, people with localised disease have survival rates of approximately 65% to 75%. In people with primary ES at diagnosis, several risk factors have been identified. An age above 14 years, tumour volume more than 200 mL, more than one bone metastatic site, bone marrow metastases and additional lung metastases are correlated with a worse outcome (Ladenstein 2010). In people with localised disease, people with tumours poorly responding to chemotherapy, people with pelvic tumours and people with high lactate dehydrogenase level at diagnosis have a worse prognosis (Bacci 2003; Cotterill 2000). Despite more intensive chemotherapy, 30% to 40% of people with ES will have recurrence of disease. For people with metastatic disease, overall survival is lower than 30% (Cotterill 2000; Ladenstein 2010; Potratz 2012; Rodriguez‐Galindo 2008).
Relapse of ES occurs at a medium of 1.6 to 2.3 years after starting initial treatment (Bacci 1989; Rodrigues‐Galindo 2007), though also very late recurrences more than 16 years after treatment of a primary tumour have been reported (Hanna 2008). About 40% to 70% of recurrences are metastatic only, followed by combined local and metastatic disease (Bacci 1989; Barker 2005; Rodrigues‐Galindo 2007; Stahl 2011). Isolated local recurrences occur less frequently and are associated with a poor chemotherapeutic response (Lin 2007). Less than 30% of people with recurrent ES are alive at 24 months and less than 10% are alive at 48 months (Barker 2005; Cotterill 2000; Shankar 2003; Stahl 2011). Higher survival of people with recurrences seems to be associated with type of relapse and site of metastases, treatment of relapse, response to second‐line therapy, relapse more than two years after diagnosis and no metastases at initial diagnosis (Bacci 2003; Barker 2005; Lin 2007; Shankar 2003).
Description of the intervention
The poor outcome for people with recurrence of disease has led to the use of high‐dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) in those people who achieved second complete remission after second‐line treatment (Bacci 2003; Barker 2005; Burdach 2003; Gardner 2008; McTiernan 2006; Shankar 2003). This seems theoretically a good treatment option to treat minimal residual disease and to improve survival rate after recurrence of disease.
HDC and AHCT are also used in people with metastatic disease and in people after relapse of disease with less than complete remission. However, these interventions are beyond the scope of this review.
How the intervention might work
After multi‐modality treatment including re‐induction chemotherapy, majority of people still harbour micro‐metastatic deposits. The hypothesis is that HDC or myeloablative conditioning regimens may overcome resistance to standard multi‐agent chemotherapy. Besides destroying the ES cells, HDC also ablates the bone marrow reserve. Therefore, HDC is always followed by haematopoietic cell transplantation.
Why it is important to do this review
The relative benefit of HDC followed by hematopoietic cell rescue in recurrent disease is still controversial. However, this treatment is associated with severe toxicity and adverse effects, including mucositis, metabolic problems and long‐lasting bone marrow aplasia with the risk of life‐threatening bleeding and infection (Burdach 2003; Gardner 2008). Some studies have reported improved disease‐free survival (Al‐Faris 2007; Barker 2005; McTiernan 2006), although other studies showed no durable benefit over conventional therapies (Gardner 2008; Shankar 2003). This systematic review will contribute to the knowledge about the efficacy of HDC followed by AHCT in children, adolescents and young adults with first recurrence of ES.
Objectives
To assess the efficacy of HDC with AHCT versus standard‐dose chemotherapy in improving event‐free survival, overall survival, quality adjusted survival and progression‐free survival of children, adolescents and young adults with first recurrence of ES and to determine the toxicity of the treatment.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with standard‐dose chemotherapy for children, adolescents and young adults with recurrence of ES.
Types of participants
Children, adolescents and young adults (aged less than 30 years at the date of diagnostic biopsy) with an earlier diagnosis of ES confirmed by pathology and with a first relapse of the disease. We will exclude people who received HDC with AHCT in the primary treatment. We will include studies that also include people who are not eligible for inclusion in this review (e.g. people older than 30 years at tumour diagnosis), if data for only the eligible participants are available.
Types of interventions
HDC with AHCT as part of second‐line treatment versus conventional standard‐dose chemotherapy. We will define HDC as chemotherapy that ablates the person's bone marrow reserves and creates an absolute requirement for stem cell rescue. We will define standard‐dose chemotherapy as chemotherapy at a lower dose than HDC that does not require stem cell rescue. We will also include studies that add an immunotherapy to HDC with AHCT.
Types of outcome measures
Outcomes listed here are not used as criteria for including studies, but are the outcomes of interest within studies identified for inclusion.
Primary outcomes
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Event‐free survival (as defined by the authors of the original study).
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Overall survival (as defined by the authors of the original study).
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Toxicity of the treatment (as defined by the authors of the original study).
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Quality‐adjusted survival (as defined by the authors of the original study).
Secondary outcomes
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Progression‐free survival (as defined by the authors of the original study).
Search methods for identification of studies
We will use the Cochrane Childhood Cancer Group's methods in the review (Module CCG). We will not apply any language restrictions. We will update the searches every two years. The Cochrane Childhood Cancer Review Group will run the searches in the Cochrane Central Library of Controlled Trials (CENTRAL), MEDLINE and EMBASE; the review authors will run all other searches.
Electronic searches
We will search the following electronic databases:
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CENTRAL (latest issue);
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MEDLINE in PubMed (from 1966 to present);
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EMBASE (Ovid; from 1980 to present).
The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in Appendix 1; Appendix 2; and Appendix 3.
Searching other resources
We will locate information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We also scan the conference proceedings of the International Society for Paediatric Oncology (SIOP; 2009 to 2013), the American Society of Pediatric Hematology/Oncology (ASPHO; 2009 to 2013), the American Society for Blood and Marrow Transplantation (ASBMT; 2009 to 2013), the European Society for Blood and Marrow (EBMT; 2009 to 2013), the Connective Tissue Oncology Society (CTOS; 2009 to 2013) and the European Musculo‐Skeletal Oncology Society (EMSOS; 2009 to 2013); we will perform these searches electronically if available or by handsearching. We will scan ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/en/) for ongoing trials.
Data collection and analysis
Selection of studies
After applying the search strategy, two review authors will independently identify studies meeting the inclusion criteria for this review. We will resolve discrepancies between authors by discussion. If we cannot reach consensus, we will achieve final resolution using a third‐party arbitrator. We will obtain the complete article of any study that seems to meet the inclusion criteria in accordance with the title or the abstract, or both. We will produce a 'Characteristics of included studies' table and include detailed information for each study. We will clearly state details of the reasons for exclusion of any study considered for the review in the 'Characteristics of excluded studies' table. We will include a PRISMA flow diagram of the selection of studies in the review. If there are multiple reports of the same study, we will use the most recent report as the primary publication; we will check the other available reports for data not reported in the primary publication.
Data extraction and management
Two review authors will independently perform data extraction using standardised forms. We will resolve discrepancies between review authors by discussion. If we cannot reach consensus, we will achieve final resolution using a third party arbitrator. We will extract data on the characteristics of participants (e.g. age, gender and other known risk factors in participants (tumour volume, primary metastatic disease, time of relapse after primary diagnosis, type of relapse and sites of metastases, response to second‐line therapy)), interventions, outcome measures, study design, length of follow‐up, details of funding sources and declaration of interests for each included study.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias in included studies (i.e. selection bias, performance bias, detection bias (for each outcome separately), attrition bias (for each outcome separately), reporting bias and other bias). We will use the risk of bias items and definitions of low risk of bias, unclear risk of bias and high risk of bias as described in the module of the Childhood Cancer Group (Module CCG), which are based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve discrepancies between review authors by discussion. If we cannot reach consensus, we will achieve final resolution using a third‐party arbitrator. We will take into account the risk of bias in included studies in the interpretation of the review's results.
Measures of treatment effect
We will analyse dichotomous variables using risk ratios (RR). We will analyse survival using hazard ratios (HR). We will use Parmar's method if HRs have not been explicitly presented in the study (Parmar 1998). We will present all results with the corresponding 95% confidence interval (CI).
Dealing with missing data
When relevant data regarding study selection, data extraction and risk of bias assessment are missing, we will attempt to contact the study authors to retrieve the missing data. We will extract data by the allocated intervention, irrespective of compliance with the allocated intervention, in order to allow an intention‐to‐treat analysis. If this is not possible, we will state this and we will perform an 'as treated' analysis.
Assessment of heterogeneity
We will assess heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity (i.e. the I2 statistic). In the absence of significant heterogeneity (I2 less than 50%) (Higgins 2011), we will use a fixed‐effect model for the estimation of treatment effects. Otherwise, we will explore possible reasons for the occurrence of heterogeneity and take appropriate measures, such as using a random‐effects model.
Assessment of reporting biases
In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we will assess reporting bias by constructing a funnel plot where there are a sufficient number of included studies (i.e. at least 10 studies included in a meta‐analysis). When there are fewer studies, the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011).
Data synthesis
We will enter data into the Review Manager 5 software (RevMan 2012), as provided by The Cochrane Collaboration and undertake analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will include outcome measures only if it was the intention of the study to perform the necessary assessments in all randomised participants (i.e. not only optional or only performed in some centres). When the results of a particular outcome measure are available for less than 50% of the participants of a study, due to the associated high risk of attrition bias, we will not report the results of this outcome measure. We will pool results only if both treatment groups are comparable, including the definition of outcomes used. We will provide a descriptive summary for studies for which pooling of results is not possible. We do not expect multi‐arm studies (i.e. including more than two treatment groups); however, if we include these studies, we will take appropriate measures as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will analyse historical CCTs separately. We will analyse studies that compare immunotherapy plus HDC with a AHCT.
For each comparison, we will prepare a 'Summary of findings' table using the GRADEprofiler software in which we plan to present the following outcomes: event‐free survival, overall survival, progression‐free survival, quality adjustes survival and toxicity of the treatment. Two review authors will independently assess the quality of the evidence using the five GRADE considerations (i.e. study limitations, inconsistency, indirectness, imprecision and publication bias).
Subgroup analysis and investigation of heterogeneity
We will not perform subgroup analyses.
Sensitivity analysis
For all outcomes for which pooling is possible, we will perform sensitivity analyses for all risk of bias criteria separately. We will exclude studies with a high risk of bias or unclear risk of bias and compare the results of studies with a low risk of bias with the results of all available studies.
