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. 2021 Sep 2;9(9):CD011405.
doi: 10.1002/14651858.CD011405.pub2.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma

Lianne M Haveman  1 , Roelof van Ewijk  1 , Elvira C van Dalen  1 , Willemijn B Breunis  2 , Leontien Cm Kremer  1   3 , Henk van den Berg  3 , Uta Dirksen  4 , Johannes Hm Merks  1   3
Affiliations

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma

Lianne M Haveman et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

UD, HvdB: contributed to one of the included studies; neither review author was involved in data extraction, risk of bias or GRADE assessment

None known for the other members of the review team

Figures

1
1
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
2
2
3
3
Forest plot of comparison: 1 Survival for primary pulmonary metastatic Ewing sarcoma, outcome: 1.1 Event‐free survival (intention‐to‐treat analysis).
1.1
1.1. Analysis
Comparison 1: Survival for primary pulmonary metastatic Ewing sarcoma, Outcome 1: Event‐free survival (intention‐to‐treat analysis)
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD011405

References

References to studies included in this review

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    1. Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation, Radiation Therapy, and/or Surgery in Treating Patients With Ewing's Sarcoma. ClinicalTrials.gov identifier: NCT00020566.
    1. Dirksen U, Brennan B, Le Deley MC, Cozic N, den Berg H, Bhadri V, et al, Euro-EWING 99 and Ewing 2008 Investigators. High-dose chemotherapy compared with standard chemotherapy and lung radiation in Ewing sarcoma with pulmonary metastases: results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial, and EWING 2008. Journal of Clinical Oncology 2019;37(34):3192-202. [DOI: 10.1200/JCO.19.00915] - DOI - PMC - PubMed
    1. Study in Localized and Disseminated Ewing Sarcoma (EWING2008). ClinicalTrials.gov identifier: NCT00987636.

References to studies excluded from this review

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Meyers 2001 {published data only}
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Oberlin 2006 {published data only}
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References to studies awaiting assessment

Dirksen 2020 {published data only}
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