유잉 육종이 처음 재발한 소아, 청소년 및 젊은 성인을 위한 고용량 화학 요법 후 자가 조혈 세포 이식
초록
배경
유잉 육종은 소아에서 두 번째로 흔한 원발성 뼈 악성 종양으로 장골과 골반에서 자주 발생하는 고형 종양입니다. 연간 100만 명당 4.5명의 발병률이 보고되며 12세에 100만 명당 11명의 최고 발병률을 보입니다. 보다 집중적인 화학 요법에도 불구하고 유잉 육종을 앓고 있는 젊은이의 30~40%는 질병이 재발합니다. 유잉 육종이 재발한 젊은이의 30% 미만이 24개월에 생존하고 10% 미만이 48개월에 생존합니다. 고용량 화학 요법(HDC)에 이어 자가 조혈 세포 이식(AHCT)이 다양한 고형 종양을 가진 다양한 소아 그룹에서 사용됩니다. 가설은 HDC 요법이 표준 다화학 요법에 대한 내성을 극복할 수 있고 이러한 방식으로 최소 잔류 질병을 근절할 수 있고 질병의 첫 번째 재발 후 개선된 생존으로 이어질 수 있다는 것입니다.
목적
유잉 육종의 첫 번째 재발이 있는 소아, 청소년 및 젊은 성인에서 무사건 생존, 전체 생존, 질 조정 생존 및 무진행 생존을 개선하는 데 AHCT를 사용한 HDC와 기존 화학요법의 효능을 평가하고 다음을 결정합니다. 치료의 독성.
검색 전략
2020년 1월 CENTRAL, MEDLINE, Embase, SIOP, ASPHO, CTOS, ASBMT, EBMT, EMSOS의 회의록과 2개의 임상 시험 레지스트리를 검색했습니다. 또한 관련 기사의 참고 문헌 목록과 문헌고찰 기사를 검색했습니다.
선정 기준
유잉 육종이 처음으로 재발한 어린이, 청소년 및 젊은 성인(진단 생검 날짜에 최대 30세)을 대상으로 HDC와 AHCT의 효과를 기존 화학요법과 비교한 무작위 대조 시험(RCT) 또는 (역사적) 대조 임상 시험(CCT)을 포함할 계획이었습니다.
자료 수집 및 분석
Cochrane에서 기대하는 표준 방법론적 절차를 사용했습니다.
주요 결과
적격한 연구를 식별하지 못했습니다.
연구진 결론
적격한 연구를 확인하지 못했기 때문에 유잉 육종의 첫 번째 재발이 있는 어린이, 청소년 및 젊은 성인에서 AHCT를 사용한 HDC의 효능 및 독성에 대한 어떠한 결론도 도출할 수 없습니다. 더 높은 수준의 연구가 시급합니다.
PICOs
쉬운 말 요약
유잉 육종의 첫 번째 재발이 있는 소아, 청소년 및 젊은 성인을 위한 고용량 화학요법(HDC) 및 자가 조혈 세포 이식(AHCT)
질문 검토
HDC와 AHCT가 유잉 육종의 첫 재발을 보이는 어린이, 청소년 및 젊은 성인에서 기존 화학요법보다 무사건 생존, 전체 생존, 질 조정 생존 및 무진행 생존을 개선했는지 여부에 대한 근거를 찾고 있었습니다. 또한 이러한 치료로 인해 발생하는 부작용을 찾고 있었습니다.
배경
유잉 육종은 뼈와 연조직, 특히 장골과 골반에 발생하며 주로 어린이, 청소년 및 젊은 성인에게 발생하는 종양입니다. 방사선 유무에 관계없이 수술 후 화학 요법이 도입된 이후로 유잉 육종 환자의 결과가 개선되었습니다. 그러나 개선된 화학 요법에도 불구하고 질병이 진행되거나 재발하여 결국 사망하는 사람들이 너무 많습니다. 유잉 육종이 처음 재발한 사람들은 예후가 좋지 않습니다. 10명 중 3명 미만의 젊은이가 24개월에 여전히 생존하고 10명 중 1명 미만이 48개월에 생존합니다. 이러한 사람들에게는 개선된 치료가 필수적입니다. 고용량 화학요법(HDC)에 이어 자가 조혈 세포 이식(AHCT, 골수 재건을 위한 정맥내 주입)은 다양한 종양이 있는 젊은 사람들에게 성공적으로 사용됩니다. 이론적으로 남아있는 적은 수의 암세포를 치료하고 유잉 육종의 첫 재발 후 생존율을 향상시키는 데 좋은 선택으로 보입니다.
주요 결과
관련 학회 절차와 진행 중인 시험 등록을 포함하여 의학 문헌을 광범위하게 검색했지만 관련 연구를 찾지 못했습니다. 따라서 AHCT가 있는 HDC가 유잉 육종이 처음으로 재발한 청소년 및 젊은 성인들에게 기존 화학 요법보다 무사건 생존, 전체 생존, 질 보정 생존 또는 무진행 생존을 개선하는지 또는 부작용을 유발하는지 여부에 대해 결론을 내릴 수 없습니다. 결과는 더 많은 연구가 필요함을 보여줍니다.
근거가 얼마나 최신인지
근거는 2020년 1월까지입니다.
Authors' conclusions
Summary of findings
| High‐dose chemotherapy with autologous haematopoietic cell transplantation versus conventional chemotherapy | |
|---|---|
| Patient or population: children, adolescents, and young adults with the first recurrence of Ewing sarcoma Settings: (paediatric) oncology departments Intervention: high‐dose chemotherapy (HDC) with autologous haematopoietic cell transplantation (AHCT) Comparison: conventional chemotherapy | |
| Outcomes | Comments |
| Event‐free survival | No studies included |
| Overall survival | No studies included |
| Quality‐adjusted survival | No studies included |
| Toxicity | No studies included |
| Progression‐free survival | No studies included |
Background
Description of the condition
Ewing sarcoma is a group of solid tumours consisting of small, blue, round cell neoplasms of neuroectodermal origin. Ewing sarcoma belongs to the Ewing family of tumours. The other types of tumours in the group are primitive neuroectodermal tumour (PNET), extraosseous Ewing sarcoma (EES), and Askin's tumour (Ewing sarcoma 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 the EWS‐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). Ewing sarcoma 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, Ewing sarcoma appears in bones; however, extraosseous manifestations do occur (Gurney 2006). The disease most often occurs in children, adolescents, and young adults, with an incidence rate of 4.5 per million a year, and 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 Ewing sarcoma. With multi‐modal treatment including multi‐agent chemotherapy, surgery, and radiotherapy, young people with localised disease have survival rates of approximately 65% to 75%. Several risk factors have been identified in young people with primary Ewing sarcoma: 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 young people with localised disease, those with tumours that respond poorly to chemotherapy, those with pelvic tumours, and those with high lactate dehydrogenase level at diagnosis have a worse prognosis (Bacci 2003; Cotterill 2000). Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of disease. For those with metastatic disease, overall survival is lower than 30% (Cotterill 2000; Ladenstein 2010; Potratz 2012; Rodriguez‐Galindo 2008).
Relapse of Ewing sarcoma occurs at an average of 1.6 to 2.3 years after starting initial treatment (Bacci 1989; Rodrigues‐Galindo 2007), although very late recurrences, more than 16 years after treatment of a primary tumour, have also been reported (Hanna 2008). In case of recurrence, about 70% of people present with metastatic disease. About 15% of people have a local recurrence and about 15% of people have 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 young people with recurrent Ewing sarcoma 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 young people with recurrences seems to be associated with the type of relapse and site of the 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 young people with recurrence of disease has led to the use of high‐dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT) in those who achieved a second complete remission after second‐line treatment (Bacci 2003; Barker 2005; Burdach 2003; Gardner 2008; McTiernan 2006; Shankar 2003). Theoretically, this seems like a good treatment strategy to treat minimal residual disease, and to improve the survival rate after recurrence of disease.
How the intervention might work
After multi‐modal treatment, including re‐introduction of chemotherapy, the majority of young people will still harbour micro‐metastatic deposits. The hypothesis is that HDC, or myeloablative conditioning regimens may overcome the resistance to standard multi‐agent chemotherapy. Besides destroying the Ewing sarcoma cells, HDC also ablates the bone marrow reserve. Therefore, HDC is always followed by autologous haematopoietic cell transplantation.
Why it is important to do this review
The relative benefit of HDC followed by autologous haematopoietic cell rescue in recurrent disease is still controversial. Moreover, 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), while other studies have shown 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 Ewing sarcoma.
Objectives
To assess the efficacy of high‐dose chemotherapy with autologous haematopoietic cell transplantation versus conventional chemotherapy in improving event‐free survival, overall survival, quality‐adjusted survival, and progression‐free survival in children, adolescents, and young adults with the first recurrence of 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 first recurrence of Ewing sarcoma.
To answer our objectives, 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 were not eligible for this review due to the high risk of bias associated with other designs.
Types of participants
Children, adolescents, and young adults (younger than 30 years on the date of diagnostic biopsy) with an earlier diagnosis of Ewing sarcoma confirmed by pathology, and with a first relapse of the disease. We excluded young people who received HDC with AHCT as the primary treatment, to make the groups more comparable. Previous HDC with AHCT is also associated with a higher risk of existing and worsening toxicity. We would have 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 were available for the participants eligible for this review.
Types of interventions
HDC with AHCT as part of second‐line treatment versus conventional chemotherapy. We defined HDC as chemotherapy that ablated the person's bone marrow reserves and created an absolute requirement for stem cell rescue. We defined conventional chemotherapy as chemotherapy given at a lower dose than HDC, which did not require stem cell rescue. We planned to include studies that added an immunotherapy to HDC with AHCT, however, we did not identify any.
Types of outcome measures
We did not use the outcomes listed here as criteria for including studies; instead, these were the outcomes of interest in 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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Quality‐adjusted 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)
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's search strategy (Module CCG). We did not apply any language restrictions. The review authors ran all 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 located information about trials not registered in CENTRAL, MEDLINE, and Embase, either published or unpublished, by searching the reference lists of relevant articles and review articles. We also screened 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), and the European Musculo‐Skeletal Oncology Society (EMSOS; 2009 to 2019); we performed these searches 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 obtained full reports of any study that seemed to meet the inclusion criteria on the grounds of the title or abstract, or both, for closer inspection. As we did not include any studies, we did not produce a 'Characteristics of included studies' table. We clearly stated detailed reasons for exclusion of any full‐text study considered for the review in the 'Characteristics of excluded studies' table. We created a PRISMA flow diagram of the selection of studies in the review (Figure 1). Had there been multiple reports of the same study, we would have used the most recent report as the primary publication; we would have checked the other available reports for data not reported in the primary publication.
Flowchart for study identification and selection
Data extraction and management
We did not identify any eligible studies. As a result, we did not extract or manage data. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Assessment of risk of bias in included studies
We did not identify any eligible studies, so risk of bias assessment was not applicable. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Measures of treatment effect
Measures of treatment effect were not an issue. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Unit of analysis issues
Unit of analysis issues were not an issue. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Dealing with missing data
Missing data was not an issue in this review, but for future updates we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Assessment of heterogeneity
Heterogeneity was not an issue. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Assessment of reporting biases
We did not identify any eligible studies. Therefore, we did not construct a funnel plot to assess reporting bias. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Data synthesis
As we did not identify any eligible studies, data synthesis was not an issue. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Subgroup analysis and investigation of heterogeneity
We had not planned any subgroup analyses.
Sensitivity analysis
Sensitivity analyses were not an issue. Should we find eligible studies during future updates of this review, we will follow the methods set out in our protocol, which are available in the Differences between protocol and review section.
Summary of findings and assessment of the certainty of the evidence
We prepared a summary of findings table, in which we presented the lack of evidence for event‐free survival, overall survival, quality‐adjusted survival, toxicity, and progression‐free survival.
If we include studies during future updates, two review authors will independently assess the certainty of the evidence using the five GRADE considerations (i.e. study limitations, inconsistency, indirectness, imprecision, and publication bias).
Results
Description of studies
Results of the search
We electronically searched CENTRAL, MEDLINE, and Embase on 1 January 2020, and identified 3524 records; see Figure 1. We identified one ongoing study through the search of ClinicalTrials.gov and WHO ICTRP, on 1 January 2020. Examining conference proceedings of aforementioned organisations did not identify any other studies. After removing duplicates, we screened the titles and abstracts of 3417 records. We excluded 3376 records for the following reasons: studies were duplicates, review articles, editorials or letters, or case reports, studies did not include participants with recurrent Ewing sarcoma. We evaluated the full text of 41 studies, all of which we excluded after full‐text assessment because of an ineligible study design.
Included studies
We did not identify any studies that met our inclusion criteria.
Excluded studies
All excluded studies had an ineligible study design, i.e. not randomised controlled trials (RCT) or controlled clinical trials (CCT) comparing the effectiveness of high‐dose chemotherapy (HDC) and autologous haematopoietic cell transplantation (AHCT) with conventional chemotherapy for children, adolescents, and young adults with the first recurrence of Ewing sarcoma). See Characteristics of excluded studies for more information.
Risk of bias in included studies
As we did not include any studies, there were no studies to assess for risk of bias.
Effects of interventions
We did not identify any studies, therefore, the effects of HDC with AHCT compared with standard chemotherapy remain unclear for event‐free survival, overall survival, quality‐adjusted survival, toxicity, and progression‐free survival in children, adolescents, and young adults with the first recurrence of Ewing sarcoma. See summary of findings Table 1.
Discussion
Summary of main results
We did not identify any studies, therefore, the effects of high‐dose chemotherapy (HDC) and autologous haematopoietic cell transplantation (AHCT) compared with standard chemotherapy remain unclear for event‐free survival, overall survival, quality‐adjusted survival, toxicity, and progression‐free survival in children, adolescents, and young adults with the first recurrence of Ewing sarcoma.
In this Cochrane Review we assessed the efficacy of HDC with AHCT versus conventional 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 Ewing sarcoma and to determine the toxicity of the treatment. To answer this type of question 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 were not eligible for inclusion in this review due to the high risk of bias associated with such designs. Unfortunately no eligible studies were identified.
Overall completeness and applicability of evidence
There is currently no evidence from randomised controlled or controlled clinical trials that assess the effects of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults with the first recurrence of Ewing sarcoma.
Potential biases in the review process
We attempted to ensure that we did not overlook any relevant evidence by performing a very extensive search for randomised controlled trials, and even included non‐randomised controlled clinical studies. Therefore, it is very unlikely that we missed any eligible studies.
Agreements and disagreements with other studies or reviews
Our extensive literature search did not find any studies that were eligible for inclusion, which is in line with previously published reviews. One systematic review included all clinical studies with participants with a recurrence of Ewing sarcoma who were treated with HDC followed by AHCT. Tenetti 2018 included 24 studies, with total of 345 participants with a recurrence of Ewing sarcoma. None of the included studies were clinical trials that were either randomised or (historically) controlled. Therefore, a high level of any bias, especially selection of participants who were eligible for HDC with AHCT, might have influenced the observation by most studies that using HDC AHCT improved survival compared to conventional chemotherapy. The main conclusion was that prospective randomised controlled studies were needed to definitively define the role of HDC with AHCT in young people with a recurrence of Ewing sarcoma.
This is in line with the conclusions of this review, and a general Ewing sarcoma management review by international experts (Gaspar 2015). At the moment, we did not identify any ongoing trials.
Flowchart for study identification and selection
| High‐dose chemotherapy with autologous haematopoietic cell transplantation versus conventional chemotherapy | |
|---|---|
| Patient or population: children, adolescents, and young adults with the first recurrence of Ewing sarcoma Settings: (paediatric) oncology departments Intervention: high‐dose chemotherapy (HDC) with autologous haematopoietic cell transplantation (AHCT) Comparison: conventional chemotherapy | |
| Outcomes | Comments |
| Event‐free survival | No studies included |
| Overall survival | No studies included |
| Quality‐adjusted survival | No studies included |
| Toxicity | No studies included |
| Progression‐free survival | No studies included |
