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.
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.
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.
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.
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.
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.
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.
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.
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.
We used standard methodological procedures expected by Cochrane.
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.