High‐dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma
Abstract
Background
Ewing sarcomas are solid tumours of the bone and soft tissue, that usually affect children, adolescents, and young adults. The incidence is about three cases per million a year, with a peak incidence at 12 years of age. Metastatic disease is detected in about 20 % to 30% of people, and is typically found in the lungs, bone, bone marrow, or a combination of these. Presence of metastatic disease at diagnosis (primary metastatic disease) is the most important adverse prognostic factor, and is associated with a five‐year survival lower than 30%. High‐dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) is used in various solid tumours with unfavourable prognoses in children, adolescents, and young adults. It has also been used as rescue after multifocal radiation of metastases. The hypothesis is that HDC regimens may overcome the resistance to standard multidrug chemotherapy and improve survival rates.
Objectives
To assess the effects of high‐dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event‐free survival, overall survival, quality‐adjusted survival, and progression‐free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, and to determine the toxicity of the treatment.
Search methods
We searched CENTRAL, MEDLINE, Embase, conference proceedings from major international cancer‐related conferences, and ongoing trial registers until January 2020. We also searched reference lists of included articles and review articles.
Selection criteria
We included randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults (younger than 30 years at the date of diagnostic biopsy) with primary metastatic Ewing sarcoma.
Data collection and analysis
We used standard methodological procedures expected by Cochrane.
Main results
We identified one RCT, which investigated the effects of HDC with AHCT versus conventional chemotherapy with whole lung irradiation (WLI) in people with Ewing sarcoma metastasised to the lungs only at diagnosis. Only a selection of the participants were eligible for our review (N = 267: HDC with AHCT group N = 134; control group N = 133).
There may be no difference in event‐free survival between the two treatment groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low‐certainty evidence). We downgraded one level each because of study limitations and imprecision. Overall survival and toxicity were not reported separately for the participants eligible for this review, while quality‐adjusted survival and progression‐free survival were not reported at all. We did not identify any studies that addressed children, adolescents, and young adults with Ewing sarcoma with metastases to other locations.
Authors' conclusions
In people with Ewing sarcoma with primary metastases to locations other than the lungs, there is currently no evidence from RCTs or CCTs to determine the efficacy of HDC with AHCT compared to conventional chemotherapy.
Based on low‐certainty evidence from one study (267 participants), there may be no difference in event‐free survival between children, adolescents, and young adults with primary pulmonary metastatic Ewing sarcoma who receive HDC with AHCT and those who receive conventional chemotherapy with WLI.
Further high‐quality research is needed. Results are anticipated for the EuroEwing 2008R3 study, in which the effects of HDC with treosulfan and melphalan followed by AHCT on survival, in people with Ewing sarcoma with metastatic disease to bone, other sites, or both were explored. Achieving high‐quality studies in a selection of people with rare sarcoma requires long‐term, multi‐centre, international participant inclusion.
PICOs
Plain language summary
High‐dose chemotherapy and haematopoietic cell transplantation for children, adolescents, and young adults with metastatic Ewing sarcoma at diagnosis
Review question
We were looking for evidence on whether high‐dose chemotherapy plus autologous haematopoietic cell transplantation (intravenous infusion of stem cells collected previously from the patient to re‐establish bone marrow) improved event‐free survival, overall survival, quality‐adjusted survival, and progression‐free survival better than conventional chemotherapy in children, adolescents, and young adults with primary metastatic Ewing sarcoma (cancer that has spread to other parts of the body at time of diagnosis). We were also looking for adverse effects that occurred because of these treatments.
Background
Ewing sarcoma is a tumour that usually occurs in the bone and soft tissue of children and young adults. People with metastatic Ewing sarcoma at diagnosis have a poor chance of survival. Less than 30% of affected people survive after five years. People with solitary lung metastases have a better chance of survival (50% survival after five years). Current treatment consists of multidrug chemotherapy combined with surgery, radiotherapy, or both. Improved therapy is essential for these people.
We conducted this review to find out whether high‐dose chemotherapy, combined with autologous haematopoietic cell transplantation can help to improve survival in children, adolescents, and young adults with metastatic Ewing sarcoma at diagnosis, compared to conventional chemotherapy.
Study characteristics
We identified one study (267 participants, who were included over a 15‐year period, from 144 international centres) that compared high dose chemotherapy plus autologous haematopoietic cell transplantation with conventional chemotherapy and whole lung irradiation in children, adolescents, and young adults with Ewing sarcoma with pulmonary metastases at diagnosis.
Key results
In young people with pulmonary metastatic Ewing sarcoma at diagnosis, low‐certainty evidence from one study found no clear difference between treatment groups in event‐free survival. There were no data available for overall survival, quality‐adjusted survival, adverse effects, or progression‐free survival. We did not find any studies that addressed children, adolescents, and young adults with Ewing sarcoma that had metastasised to locations besides the lungs at diagnosis. We need high‐quality research before definite conclusions can be made.
Certainty of the evidence
The certainty of the evidence was low.
How current is the evidence
The evidence is current to January 2020.
Authors' conclusions
Summary of findings
| High‐dose chemotherapy followed by autologous haematopoietic cell transplantation compared with conventional chemotherapy plus whole lung irradiation |
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| Patient or population: children, adolescents, and young adults with primary metastatic Ewing sarcoma Settings: (paediatric) oncology departments Intervention: high‐dose chemotherapy followed by autologous haematopoietic cell transplantation Comparison: conventional chemotherapy plus whole lung irradiation |
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| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments |
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| Assumed risk with CC + WLI | Corresponding risk with HDC + AHCT |
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| Event‐free survival (reported as number of participants with progression, relapse, second malignancy, or death, whatever the cause) Follow‐up not mentioned
| 537 per 1000a | 473 per 1000 (365 to 594) | HR 0.83 (0.59 to 1.17) | 267 | ⊕⊕⊝⊝
| Only pulmonary or pleural metastases, without other distant metastases, were included in this study. Note that due to limitations of the software for this table, event‐free survival is presented as number of participants with an event. Results in the different age groups (< 12 years, 12 to 18 years, and 18 to 25 years) were similar to the overall results described here, including the GRADE assessment. |
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| Overall survival | ‐ | ‐ | ‐ | ‐ | ‐ | Data for participants under the age of 30 years were not reported separately. |
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| Quality‐adjusted survival | ‐ | ‐ | ‐ | ‐ | ‐ | No information was provided for quality‐adjusted survival. |
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| Toxicity | ‐ | ‐ | ‐ | ‐ | ‐ | Data for participants under the age of 30 years were not reported separately. |
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| Progression‐free survival | ‐ | ‐ | ‐ | ‐ | ‐ | No information was provided for progression‐free survival. |
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| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AHCT: autologous haematopoietic cell transplantation; CC: conventional chemotherapy; CI: confidence Interval; HDC: high‐dose chemotherapy; HR: hazard ratio; WLI: whole lung irradiation |
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| GRADE Working Group grades of evidence |
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| aThe assumed risk was based on the prevalence in the control group of the included study. | |||||||
Background
Description of the condition
Ewing sarcomas are solid tumours consisting of small, blue, round cells with minimal stroma that may exhibit varying degrees of neural differentiation. They appear mainly in bones, and less frequently in soft tissues (Gorlick 2013; Kauer 2009; Ordóñez 2009). Ewing sarcoma 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 (Ewing sarcoma of the chest wall). The tumours are thought to arise from the same primordial stem cell, and are defined by the presence of EWSR1‐ETS gene re‐arrangements. In 85% to 90% of cases, the ETS transcription factor fuses with FLI, resulting in the EWS‐FLI fusion protein. This t(11;22)(q24;q12) chromosomal translocation can take place at different intron‐exon sites. Less frequently, in about 10% of people, EWSR1 fusions with other members of the ETS family occur, most commonly with ERG. More than 18 different translocations have been described. Occasionally, fusions between EWSR1 and non‐ETS gene family members are seen (Delattre 1994; Potratz 2012). Ewing sarcoma most often occurs in children, adolescents, and young adults, and is the second most common bone cancer, with a slight male predominance (Gurney 1999). The incidence is about three cases per million a year (Esiashvili 2008). In children, the incidence is higher (4.5 per million), with a peak incidence of 11 per million at the age of 12 years (Van den Berg 2008). Ewing sarcoma often occurs in the long bones and pelvis (Esiashvili 2008; Teicher 2011; Van den Berg 2008). Metastatic disease is typically found in the lungs (50%), bone (28%), or bone marrow (13% (Cangir 1990)). The combination of lung metastases with bone metastases is the most frequently seen (45% (Ladenstein 2010)). Isolated pulmonary lung metastases are found in about 25% of the people with Ewing sarcoma (Dirksen 2019). The presence of metastases at diagnosis is the most important adverse prognostic factor, and is detected in about 20% to 30% of people (Cotterill 2000; Esiashvili 2008; Jenkin 2001; Lee 2011). Multivariable analysis of the most recent European Euro‐Ewing‐99 trial, performed in people with primary disseminated multifocal Ewing sarcoma, showed factors at diagnosis that significantly correlated with a worse outcome: people older than 14 years, tumour volume of 200 mL or greater, more than one bone metastatic site, bone marrow metastases, and additional lung metastases (Ladenstein 2010). Additional adverse clinical prognostic factors have been found in people with non‐metastatic Ewing sarcoma, such as site of the primary tumour (axial located tumours do worse), poor histological response (10% or greater viable tumour cells), and elevated serum lactate dehydrogenase level (Bacci 2000; Cotterill 2000). Besides participant characteristics, local therapy of involved sites affects outcome (Haeusler 2010). Five‐year survival in people with primary metastatic disease is less than 30%, compared with a survival expectancy of people with isolated pulmonary metastases of about 50%, and people with localised disease of 75% (Gorlick 2013; Ladenstein 2010; Dirksen 2019).
Description of the intervention
High‐dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in various solid tumours with an unfavourable prognosis in children, adolescents, and young adults (Carli 2004; Claviez 2008; Matthay 1999; Spreafico 2008). It has also been used as rescue after multifocal radiation of metastases (Burdach 1993). The hypothesis is that myeloablative conditioning regimens may overcome the resistance of Ewing sarcoma cells to standard multidrug chemotherapy and improve survival rate.
How the intervention might work
While overt metastatic disease is prognostic, it is clear that most people with metastatic disease (also people with localised disease) harbour micro‐metastatic deposits. The hypothesis is that HDC (also known as myeloablative conditioning regimens), may overcome the resistance to standard multi‐agent chemotherapy. HDC ablates the person's bone marrow reserve, which is an important adverse effect that requires haematopoietic cell transplantation. To improve the survival rate of people with metastatic Ewing sarcoma at presentation, several studies have used HDC followed by AHCT (Al‐Faris 2007; Burdach 2000; Drabko 2005; Fraser 2006; Kushner 2001; Meyers 2001; Rosenthal 2008).
Why it is important to do this review
The value of HDC followed by AHCT in the treatment of people with primary metastatic Ewing sarcoma has not been established. This treatment is very intensive, and may be associated with important toxicity and adverse effects, including severe mucositis, metabolic problems, and long lasting bone marrow aplasia, with the risk of life‐threatening bleeding and infection. No systematic reviews have been identified that have investigated whether HDC followed by AHCT contributes to a better survival rate (event‐free survival, or overall survival, or both) in people with primary metastatic Ewing sarcoma.
Objectives
To assess the effects of high‐dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event‐free survival, overall survival, quality‐adjusted survival, and progression‐free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, 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 high‐dose chemotherapy (HDC) and autologous haematopoietic cell transplantation (AHCT) with conventional chemotherapy for children, adolescents, and young adults with primary metastatic Ewing sarcoma.
Types of participants
Children, adolescents, and young adults (younger than 30 years old at the date of diagnostic biopsy) with a diagnosis of Ewing sarcoma, confirmed by pathology, and evidence of primary distant metastases. We considered people to have distant metastases when the tumour was detected clinically or radiographically in one or more sites distant from the primary site, and outside the regional lymph nodes. We only included studies that also included people who were not eligible for this review (e.g. people older than 30 years at tumour diagnosis) if separate data for the eligible people were available.
Types of interventions
HDC with AHCT (i.e. the intervention treatment) and conventional chemotherapy (i.e. the comparator treatment).
We defined HDC as chemotherapy that ablated the young person's bone marrow reserves and created an absolute requirement for stem cell rescue. We defined conventional chemotherapy as chemotherapy administered at a lower dose than HDC, which did not require stem cell rescue. We planned to include studies that added immunotherapy to HDC with AHCT; we did not identify any.
Types of outcome measures
Outcomes listed here were not used as criteria for the selection of studies, but were outcomes of interest.
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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Quality‐adjusted survival (as defined by the authors of the original study)
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Toxicity (i.e. adverse effects) of the treatment (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 used Cochrane Childhood Cancer methods in the review (Module CCG 2010). We did not impose language restrictions. The review authors ran all the searches.
Electronic searches
We searched the following electronic databases:
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Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 12) in the Cochrane Library (searched 1 January 2020);
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MEDLINE PubMed (1966 to 1 January 2020);
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Embase Ovid (1980 to 1 January 2020).
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 searched for information about trials not registered in CENTRAL, MEDLINE, and Embase, either published or unpublished, by searching the reference lists of included articles and review articles. We also scanned the conference proceedings of the International Society for Paediatric Oncology (SIOP; 2009 to 2019), the American Society of Pediatric Hematology/Oncology (ASPHO; 2009 to 2019), the Connective Tissue Oncology Society (CTOS; 2009 to 2019), the American Society for Blood and Marrow Transplantation (ASBMT; 2009 to 2019), the European Society for Blood and Marrow Transplantation (EBMT; 2009 to 2019), the European Musculo‐Skeletal Oncology Society (EMSOS; 2009 to 2019), and the American Society of Clinical Oncology (ASCO; 2009 to 2019); we searches these proceedings electronically if available, or by handsearching. We scanned ClinicalTrials.gov (www.clinicaltrials.gov; searched 1 January 2020), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; www.who.int/ictrp/en/; searched 1 January 2020) for ongoing trials.
The search strategies for the different conference proceedings and trial registries (using a combination of controlled vocabulary and text words) are shown in Appendix 4 and Appendix 5.
Data collection and analysis
Selection of studies
After the search, two review authors independently identified studies that met the inclusion criteria for this review. We resolved discrepancies between review authors by discussion. If we could not reach consensus, we achieved final resolution using a third party arbitrator. We collected the full text of any study that seemed to meet the inclusion criteria on the grounds of the title, or abstract, or both, for closer inspection. We produced a Characteristics of included studies table, and included detailed information for each study. We stated detailed reasons for exclusion of any study considered for the review in the Characteristics of excluded studies table. We created a PRISMA flow diagram of the selection process for studies in the review. If there were multiple publications of the same study, we planned to use the most recent report as the primary publication.
Data extraction and management
Two review authors independently extracted data, using standardised forms. We resolved discrepancies between review authors by discussion. If we could not reach consensus, we achieved final resolution using a third party arbitrator. We extracted data on the characteristics of participants (e.g. age, gender, known risk factors for people with metastatic disease (tumour volume, sites of metastases (lungs, bone, bone marrow, or a combination)), interventions, outcome measures, study design, length of follow‐up, details of funding sources, and declaration of interests for the included study.
Assessment of risk of bias in included studies
Two review authors independently assessed the risk of bias in the included study (i.e. selection bias, performance bias, detection bias (for each outcome separately), attrition bias (for each outcome separately), reporting bias, and other bias). We used 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 Cochrane Childhood Cancer (Module CCG 2010), which were based on the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved discrepancies between review authors by discussion. If this was impossible, we achieved final resolution using a third party arbitrator. We took into account the risk of bias in the included study in the interpretation of the review's results.
Measures of treatment effect
We analysed survival using hazard ratios (HR). HRs were presented in the included study, so we didn't need to use Parmar's method. However, if for future updates this is needed, more details can be found in Parmar 1998. All results were presented with the corresponding 95% confidence interval (CI). If dichotomous data had been available, we would have analysed them using risk ratios (RR).
Unit of analysis issues
We did not identify any unit of analysis issues in this review and we don't expect them with future updates, but if they do occur, we will follow methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
When relevant data regarding study selection, data extraction, and risk of bias assessment were missing, we attempted to contact the study authors to retrieve missing data. We extracted data by the allocated intervention, irrespective of compliance with the allocated intervention, in order to enable an intention‐to‐treat analysis. If this was not possible, we stated this, and we performed an as treated analysis.
Assessment of heterogeneity
We had planned to investigate heterogeneity using visual inspection of the forest plots, and by using a formal statistical test for heterogeneity (i.e. the I² statistic). We defined significant heterogeneity as I² of 50% or more, but as we only included one study, this was not applicable (Higgins 2011).
Assessment of reporting biases
In addition to the evaluation of reporting bias, as described in the Assessment of risk of bias in included studies, we planned to assess reporting bias by constructing a funnel plot, had there been a sufficient number of included studies (i.e. at least 10 studies included in a meta‐analysis). As there was only one included study, which made the power of the test too low to distinguish chance from real asymmetry, we did not construct a funnel plot (Higgins 2011).
Data synthesis
We entered data into the Cochrane Review Manager 5 software, and undertook analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Review Manager 2020). We included 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).
Due to associated high risk of attrition bias, had the results of a particular outcome measure been available for less than 50% of the participants of a study, we would not have reported the results of this outcome measure; this was not applicable. As we only included one study, we did not pool results. If more trials are included in future updates, we will pool data if both treatment groups are comparable, including the definition of outcomes used. We did not identify any multi‐arm studies, so did not use the measures described in the Cochrane Handbook for Systematic Reviews of Interventions for this study design (Higgins 2011). We planned to analyse historical CCT's separately, but did not identify any. We planned to analyse studies that compared immunotherapy plus HDC with AHCT separately, but did not identify any.
Subgroup analysis and investigation of heterogeneity
As described in the protocol, we did not plan to conduct subgroup analyses.
Sensitivity analysis
For all outcomes for which pooling was possible, we planned to perform sensitivity analyses for all risk of bias criteria separately. Since only one study was included, this was not applicable.
Summary of findings and assessment of the certainty of the evidence
For each comparison, we prepared a summary of findings table, using GRADEpro software, in which we present the evidence for event‐free survival, overall survival, quality‐adjusted survival, progression‐free survival, and toxicity of the treatment (GRADEpro GDT). For each outcome, two review authors independently assessed the certainty of the evidence (high, moderate, low, very low) by using the five GRADE considerations (i.e. study limitations, inconsistency, indirectness, imprecision, and publication bias), as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Results
Description of studies
Results of the search
We identified 3524 records from CENTRAL, MEDLINE, and Embase, and one study from the conference proceedings; see Figure 1. We did not identify any further studies from the reference list of the included study, or ongoing studies from the trial registers.
Flow diagram of selection of studies
ASBMT: American Society for Blood and Marrow Transplantation; ASPHO: American Society of Pediatric Hematology/Oncology; CTOS: Connective Tissue Oncology Society; EBMT: American Society for Blood and Marrow Transplantation; EMSOS: European Musculo‐Skeletal Oncology Society; SIOP: International Society for Paediatric Oncology
After removing duplicates, we screened the titles and abstracts of 3419 records, excluding 3362 because they were duplicates, review articles, editorials, letters, case reports, or the studies did not include participants with primary metastatic Ewing sarcoma.
We evaluated 57 full‐text study report, one of which fulfilled the inclusion criteria (Dirksen 2019). We excluded 55 studies, and identified one study as awaiting classification.
Included studies
The characteristics of the included study are summarised in the Characteristics of included studies table.
The study, the R2pulm trial, was part of the Euro‐E.W.I.N.G. 99 study (ClinicalTrials.gov identifier: NCT00020566) and the consecutive EWING 2008 study (ClinicalTrials.gov identifier: NCT00987636). The R2pulm trial was an international multicentre trial, including 14 countries, performed by 5 cooperative groups: Children`s Oncology Group, European Organisation for Research and Treatment of Cancer, Gesellschaft fur Paediatrische Onkologie und Haematologie, French Society of Pediatric Oncology and French Sarcoma Group, and the Children’s Cancer and Leukaemia Group. All eligible people had histological confirmation of Ewing sarcoma, had lung or pleural metastases at diagnosis and no metastatic lesions at other sites. Of note, eligible people were less than 50 years of age. Therefore, data of this study will only be included if described separately for our study population if people were less than 30 years of age. People received induction chemotherapy with 6 induction chemotherapy courses with vincristine, ifosfamide, doxorubicin and etoposide (VIDE), followed by 1 vincristine, actinomycin‐D, ifosfamide (VAI) course before randomisation to high dose chemotherapy with busulfan and melphalan (BuMel) followed by stem cell rescue or they received 7 VAI courses (=conventional chemotherapy (CC)) combined with WLI. Patients were enrolled between February 2000 and December 2015 from 144 centres from 14 countries.
The study included 267 people of 25 years of age and younger, no information on mean or median age for these patients was provided. 133 people were randomised to the intervention group (i.e. HDC and AHCT) and 134 people to the control group (i.e. CC and WLI). No specific numbers on gender were mentioned for people ≤ 25 years (in the total study group it was 59% males). No specific data on follow‐up were provided for patients eligible for this review (median followup for the whole study group was 8.1 years (range 0 ‐15.5)).
Excluded studies
We excluded 55 studies because of ineligible study design. See the Characteristics of excluded studies table.
Characteristics of studies awaiting classification
We identified one study that was not yet published in full text, and which we added to the Characteristics of studies awaiting classification table (Dirksen 2020).
Risk of bias in included studies
The risk of bias assessment and support of judgements of the included study can be found in the Characteristics of included studies table and Figure 2.
Allocation
To evaluate selection bias, we assessed random sequence generation and allocation concealment. Both were done in an adequate manner, and thus, we considered the risk of selection bias to be low.
Blinding
To evaluate performance bias, we assessed blinding of participants and personnel. To evaluate detection bias, we evaluated blinding of outcome assessors for each separate outcome.
We judged the risk of performance bias to be high, since blinding of therapy could not be achieved because of the obvious differences between treatments. We judged the risk of detection bias for event‐free survival as unclear, as no information on the blinding of outcome assessors was provided.
Incomplete outcome data
To evaluate attrition bias, we assessed incomplete outcome data for each outcome separately.
Separate data for the review's eligible participants were not provided, but out of 287 participants in the total study group, 11 in the intervention group and 7 in the control group were lost to follow‐up. Even if all the participants lost to follow‐up were 25 years old or younger, the risk of attrition bias for would still be low, as a maximum of 11/133 (8%) of the intervention group and 7/134 (5%) in the control group would be lost to follow‐up.
Selective reporting
To evaluate reporting bias, we assessed selective reporting.
The study protocol was available, and all of the study’s prespecified (primary and secondary) outcomes of interest were reported as prespecified. We judged the risk of selective reporting to be low, although not all outcomes were eligible for inclusion in this review.
Other potential sources of bias
To evaluate other potential sources of bias, we assessed: block randomisation in unblinded trials, baseline imbalance for important prognostic factors, differences between treatment groups in length of follow‐up, and other potential biases.
We judged the risk of other potential sources of bias to be high.
Effects of interventions
High‐dose chemotherapy followed by autologous haematopoietic cell transplantation compared with conventional chemotherapy plus whole lung irradiation
Primary outcomes
Event‐free survival (EFS)
EFS was defined as the time from randomisation to the time of the first event assessed by the investigator, defined as progression, relapse, second malignancy, or death, whatever the cause. Hazard ratios (HR) and 95% confidence interval (CI) of different age groups were presented, so Parmar analyses were not needed. There was no clear evidence of a difference in EFS between the intervention (133 participants) and control groups (134 participants) overall (HR 0.83, 95% CI 0.59 to 1.17; P = 0.28; 1 study, 267 participants; low‐certainty evidence; Analysis 1.1; Figure 3), or for the different age groups (≤ 12 years, 12 to 18 years, 18 to 25 years).
Forest plot of comparison: 1 Survival for primary pulmonary metastatic Ewing sarcoma, outcome: 1.1 Event‐free survival (intention‐to‐treat analysis).
Overall survival
Data on overall survival, for participants under the age of 30 years, were not reported separately.
Quality‐adjusted survival
Quality‐adjusted survival was not reported.
Toxicity of the treatment:
Data on toxicity, for participants under the age of 30 years, were not reported separately.
Secondary outcomes
Progression‐free survival
Progression‐free survival was not reported.
Discussion
Summary of main results
We included one study, the R2pulm trial (267 participants), which investigated the effects of high‐dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) compared to conventional chemotherapy combined with whole lung irradiation in young people with Ewing sarcoma and isolated pulmonary metastatic disease at diagnosis (Dirksen 2019).
There was no clear evidence of a difference in event‐free survival between the intervention and control groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low‐certainty evidence). Overall survival and toxicity were not separately reported for the review's eligible participants, while quality‐adjusted survival and progression‐free survival were not reported at all. See summary of findings Table 1.
In this Cochrane review we assessed the efficacy of HDT with AHCT compared to conventional chemotherapy in children, adolescents and young adults with a primary metastatic Ewing sarcoma. Only one study fulfilled the inclusion criteria, which impeded meta‐analysis of outcomes.
The study, the R2pulm trial, investigated the value of HDC with AHCT compared to conventional chemotherapy combined with whole lung irradiation in people with EwS and isolated pulmonary metastatic disease at diagnosis. It included 267 people eligible for inclusion in this review: 133 people were randomised to the intervention group (i.e. HDC and AHCT) and 134 people to the control group (i.e. CC and WLI). No clear evidence of a difference in EFS between the intervention and control group was identified (HR 0.83, 95% CI 0.59 to 1.17). Overall survival and toxicity were not separately reported for the eligible patients, while quality adjusted survival and progression‐free survival were not reported at all.
Overall completeness and applicability of evidence
The most important limitation was the lack of available data. We only identified one study, encompassing 267 participants with isolated pulmonary metastases. Because of the lack of studies, we are unable to draw any conclusions for children, adolescents, and young adults with Ewing sarcoma with metastases to other locations. The results of the international Ewing 2008R3 trial are expected. This trial evaluated the effects of HDC with treosulfan and melphalan, followed by AHCT on the main endpoints of event‐free and overall survival in people with Ewing sarcoma and metastases to bone, other sites, or both (Dirksen 2020).
For children, adolescents, and young adults with isolated pulmonary metastases, data for event‐free survival showed no clear evidence of a difference between treatment groups. However, 'no evidence of effect' is not the same as 'evidence of no effect'. In this review, it may be due to the fact that the number of included participants was too small to detect a difference between the treatment groups (that is, low power).
Importantly, data were not available for all outcomes of interest for prespecified eligible participants (data were available for a subgroup of people aged under 25 years), i.e. overall survival, quality‐adjusted survival, toxicity, and progression‐free survival. As a result, we cannot draw conclusions regarding these outcomes, which are important in clinical practice. It should be noted that while in this review we focused on children, adolescents, and young adults (up to 30 years old), the included study also included participants up to 50 years of age. Overall survival and toxicity data were available for the whole study population. For overall survival, they did not identify clear evidence of a difference between treatment groups (unadjusted intention‐to‐treat HR of death 1.00 (95% CI 0.70 to 1.44). However, significantly more participants in the HDT with AHCT group experienced severe acute toxicities. However, we should be careful with extrapolating these results to children, adolescents, and young adults.
Quality of the evidence
The certainty of evidence was low for event‐free survival. We downgraded one level each for study limitations and imprecision. However, at this time, this is the best available evidence based on randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating the efficacy of HDT with AHCT compared to conventional chemotherapy in children, adolescents, and young adults with primary metastatic Ewing sarcoma.
Potential biases in the review process
The results of this Cochrane Review provide a clear overview of the current available evidence regarding the value of HDT with AHCT compared to conventional chemotherapy in children, adolescents, and young adults with primary metastatic Ewing sarcoma. We used a very broad search strategy to identify eligible studies. However, although it is unlikely that we missed eligible studies, we cannot completely rule out reporting bias.
Agreements and disagreements with other studies or reviews
The lack of evidence identified in this systematic review is in line with both previously published cohort studies, and general reviews. To adequately ascertain the efficacy of HDC with AHCT, the best study design, provided that the design and execution are correct, is an RCT. CCTs can also provide reliable information, keeping in mind their limitations, but other study designs are associated with a high risk of bias. Keeping in mind the limitations of these study designs, multiple large cohorts have addressed high‐dose chemotherapy with AHCT in people with primary metastatic Ewing sarcoma. All concluded that although HDC with AHCT seems promising, there remains insufficient evidence (Frohlich 1999; Gardner 2008; Ivanova 2012; Jodele 2010; Jurgens 2012; Kazantsev 2016; Ladenstein 2010; Luksch 2012; MarcusJr 1988; Oberlin 2006; Paulussen 1998; Ranft 2011; Rose 2009; Tanaka 2002). The most recently published intercontinental collaborative review about optimal and new therapy in Ewing sarcoma states that HDC with AHCT remains under debate due to insufficient evidence (Gaspar 2015).
No previous reviews specifically addressed children, adolescents, and young adults with pulmonary metastatic Ewing sarcoma undergoing high dose chemotherapy and AHCT. Dirksen 2019 provides some new insight for this specific group, as discussed in this review.
Flow diagram of selection of studies
ASBMT: American Society for Blood and Marrow Transplantation; ASPHO: American Society of Pediatric Hematology/Oncology; CTOS: Connective Tissue Oncology Society; EBMT: American Society for Blood and Marrow Transplantation; EMSOS: European Musculo‐Skeletal Oncology Society; SIOP: International Society for Paediatric Oncology
Forest plot of comparison: 1 Survival for primary pulmonary metastatic Ewing sarcoma, outcome: 1.1 Event‐free survival (intention‐to‐treat analysis).
Comparison 1: Survival for primary pulmonary metastatic Ewing sarcoma, Outcome 1: Event‐free survival (intention‐to‐treat analysis)
| High‐dose chemotherapy followed by autologous haematopoietic cell transplantation compared with conventional chemotherapy plus whole lung irradiation |
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| Patient or population: children, adolescents, and young adults with primary metastatic Ewing sarcoma Settings: (paediatric) oncology departments Intervention: high‐dose chemotherapy followed by autologous haematopoietic cell transplantation Comparison: conventional chemotherapy plus whole lung irradiation |
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| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments |
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| Assumed risk with CC + WLI | Corresponding risk with HDC + AHCT |
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| Event‐free survival (reported as number of participants with progression, relapse, second malignancy, or death, whatever the cause) Follow‐up not mentioned
| 537 per 1000a | 473 per 1000 (365 to 594) | HR 0.83 (0.59 to 1.17) | 267 | ⊕⊕⊝⊝
| Only pulmonary or pleural metastases, without other distant metastases, were included in this study. Note that due to limitations of the software for this table, event‐free survival is presented as number of participants with an event. Results in the different age groups (< 12 years, 12 to 18 years, and 18 to 25 years) were similar to the overall results described here, including the GRADE assessment. |
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| Overall survival | ‐ | ‐ | ‐ | ‐ | ‐ | Data for participants under the age of 30 years were not reported separately. |
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| Quality‐adjusted survival | ‐ | ‐ | ‐ | ‐ | ‐ | No information was provided for quality‐adjusted survival. |
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| Toxicity | ‐ | ‐ | ‐ | ‐ | ‐ | Data for participants under the age of 30 years were not reported separately. |
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| Progression‐free survival | ‐ | ‐ | ‐ | ‐ | ‐ | No information was provided for progression‐free survival. |
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| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AHCT: autologous haematopoietic cell transplantation; CC: conventional chemotherapy; CI: confidence Interval; HDC: high‐dose chemotherapy; HR: hazard ratio; WLI: whole lung irradiation |
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| GRADE Working Group grades of evidence |
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| aThe assumed risk was based on the prevalence in the control group of the included study. | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Event‐free survival (intention‐to‐treat analysis) Show forest plot | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.83 [0.59, 1.17] | |
