Autologous hematopoietic stem cell transplantation following high dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas

  • Review
  • Intervention

Authors


Abstract

Background

Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage.

Objectives

To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults.

Search methods

For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. All studies included in the original review were considered for re-evaluation in the update. We searched the electronic databases CENTRAL (2012, Issue 11) in The Cochrane Library , MEDLINE and EMBASE (05 December 2012) from their inception using the newly developed search strategy. Online trials registers and reference lists of systematic reviews were searched.

Selection criteria

Terms representing STS and autologous HSCT were required in the title or abstract. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Single-arm studies were included in addition to studies with a control arm because the number of comparative studies was expected to be very low.

Data collection and analysis

Two review authors independently extracted study data. Some studies identified in the original review were re-examined and found not to meet the inclusion criteria and were excluded in this update. For studies with no comparator group, we synthesized the results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM).

Main results

The selection process was carried out from the start of the search dates for the update. We included 57 studies, from 260 full text articles screened, reporting on 275 participants that were allocated to HDCT followed by autologous HSCT. All studies were not comparable due to various subtypes. We identified a single comparative study, an RCT comparing HDCT followed by autologous HSCT versus standard chemotherapy (SDCT). The overall survival (OS) at three years was 32.7% versus 49.4% with a hazard ratio (HR) of 1.26 (95% confidence interval (CI) 0.70 to 2.29, P value 0.44) and thus not significantly different between the treatment groups. In a subgroup of patients that had a complete response before treatment, OS was higher in both treatment groups and OS at three years was 42.8% versus 83.9% with a HR of 2.92 (95% CI 1.1 to 7.6, P value 0.028) and thus was statistically significantly better in the SDCT group. We did not identify any other comparative studies. We included six single-arm studies reporting aggregate data of cases; three reported the OS at two years as 20%, 48%, and 51.4%. One other study reported the OS at three years as 40% and one further study reported a median OS of 13 months (range 3 to 19 months). In two of the single-arm studies with aggregate data, subgroup analysis showed a better OS in patients with versus without a complete response before treatment. In a survival analysis of pooled individual data of 80 participants, OS at two years was estimated as 50.6% (95% CI 38.7 to 62.5) and at three years as 36.7% (95% CI 24.4 to 49.0). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. The one included RCT had a low risk of bias and the remaining 56 studies had a high risk of bias.

Authors' conclusions

A single RCT with a low risk of bias shows that OS after HDCT followed by autologous HSCT is not statistically significantly different from standard-dose chemotherapy. Therefore, HDCT followed by autologous HSCT for patients with NRSTS may not improve the survival of patients and should only be used within controlled trials if ever considered.

Plain language summary

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for non-rhabdomyosarcoma soft tissue sarcomas

Review question

We reviewed the evidence about the effect of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation compared to standard-dose chemotherapy on overall survival in people with non-rhabdomyosarcoma soft tissue sarcomas. We found one randomized controlled trial (RCT) comparing both treatments and 48 studies with results from transplantation only.

Background

Non-rhabdomyosarcoma soft tissue sarcomas are a group of rare cancers. People with inoperable or metastatic disease have a poor prognosis. It was believed that higher doses of chemotherapy might improve patients' survival. However, high doses of chemotherapy stop the production of blood cells in the bone marrow and are not compatible with life. Stem cells collected from people before high-dose chemotherapy can be transplanted back to the patient if the blood cell count gets too low. Due to a lack of research studies, it has not been proven that patients treated with this procedure live any longer than patients treated with standard chemotherapy. We wanted to determine whether using high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation was better or worse than standard-dose chemotherapy.

Study characteristics

The evidence is current to 5 December 2012. The single RCT that was identified compared 38 patients in the transplantation group versus 45 patients in the chemotherapy only group and was judged to have a low risk of bias (high methodological quality). The participants were 18 to 65 years old, had various types of non-rhabdomyosarcoma soft tissue sarcomas and were observed for a median follow-up time of 55 months. The rest of the studies reported results for a series of or individual transplanted patients only, with various ages, tumor types and follow up times; they all had a high risk of bias. The treatment period among studies ranged from 1994 to 2008. The single RCT and some of the other studies were funded by non-profit organizations. Three studies reported financial support by biopharmaceutical companies. Most studies did not give details of funding.

Key results

In the single RCT, the overall survival (OS) at three years was 32.7% in the transplantation group versus 49.4% in the chemotherapy only group, and this was not found to be significant. There was one case of treatment-related mortality in the transplantation group and none in the chemotherapy only group.

Quality of evidence

The overall quality of the data was based on a single RCT, which had a low risk of bias. The rest of the studies had a high risk of bias due to single-arm and retrospective study design and were not useful for comparing two treatments. Currently the research evidence indicates that patients with non-rhabdomyosarcoma soft tissue sarcomas should not be treated with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. If this treatment is offered it should be done only within clinical controlled trials and after careful consideration.

Summary of findings(Explanation)

Summary of findings for the main comparison. Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcoma
  1. 1 case series

Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcoma
Patient or population: patients with non-rhabdomyosarcoma soft tissue sarcoma
Settings: Spezialized hospital
Intervention: Autologous hematopoietic stem cell transplantation following high-dose chemotherapy
Comparison: standard-dose chemotherapy
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Standard-dose chemotherapy Autologous hematopoietic stem cell transplantation following high-dose chemotherapy
Overall survival
Follow-up: median 55 months
489 per 1000 571 per 1000
(375 to 785)
HR 1.26
(0.7 to 2.29)
83
(1 study)
⊕⊕⊕⊕
high
 
Progression-free survival
Follow-up: median 55 months
756 per 1000 849 per 1000
(681 to 955)
HR 1.34
(0.81 to 2.2)
83
(1 study)
⊕⊕⊕⊕
high
 
Treatment-related mortalitySee commentSee commentNot estimable163
(12 studies1)
⊕⊝⊝⊝
very low
case series; 15 events in 0 subjects
Health-related quality of lifeSee commentSee commentNot estimable-See commentnot reported
Disease-free survival
Follow-up: 3 years
See commentSee commentNot estimable0
(1 study1)
⊕⊝⊝⊝
very low 1
case series; 0 events in 0 subjects
Non-hematological toxicity grade 3 to 4See commentSee commentNot estimable105
(9 studies1)
⊕⊝⊝⊝
very low 1
case series; 38 events in 0 subjects
*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).
CI: Confidence interval; HR: Hazard ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors of non-epithelial extraskeletal body tissue and are classified on a histogenetic basis (Enzinger 2001). STS have a significant risk of distant metastasis in addition to the potential for locally destructive growth and recurrence. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma, which primarily affects children and young adults. In this review we investigated NRSTS which are categorized as malignant according to the World Health Organization (WHO) 2002 classification (Fletcher 2002) as adopted by the European Society for Medical Oncology (ESMO) Guidelines Working Group (ESMO 2012). This latter classification excludes the Ewing family of tumors (EFT).

NRSTS usually originate de novo and rarely from benign tumors. In most cases the pathogenesis is unknown; however, some factors have been found to be associated with the development of NRSTS (Enzinger 2001). These include exposure to ionizing radiation, environmental carcinogenic substances, oncogenic viruses and immunologic factors. Genetic factors can also play a role since some inherited diseases such as neurofibromatosis type 1 are associated with a higher risk of NRSTS (Tsao 2000).

In Western countries about four new cases of NRSTS are estimated per 100,000 population every year (ESMO 2012), with rhabdomyosarcoma and the Ewing family of tumors excluded from this statistic. STS constitute about 1% of malignancies in adults and 7% in children (NCI 2009a). Rhabdomyosarcoma represents about 50% of STS in children (Gurney 1997; Miller 1995). NRSTS are rare in both children and adults and the distribution of NRSTS differs significantly between children and adults (Table 1) according to Spunt 2006.

Table 1. Frequency of subtypes of included NRSTS in patients of young versus advanced age
  1. Estimates in the table according to Spunt 2006

Young age (< 20 years) Advanced (≥ 20 years)
Subtype%Subtype%
Synovial sarcoma7.7Leiomyosarcoma13.7
Malignant fibrous histiocytoma4.9Malignant fibrous histiocytoma10.1
Fibrosarcoma4.5Liposarcoma8.0
Liposarcoma2.8Hemangiosarcoma2.5
Epitheloid sarcoma2.0Spindle cell sarcoma2.3

Based on the Surveillance, Epidemiology and End Results (SEER) cancer statistics review (1975 to 2007) of the National Cancer Institute (NCI), in the US 10,520 new cases and 3920 deaths from STS were estimated for the year 2010 (NCI 2010a). Separate data were not available for rhabdomyosarcoma and NRSTS. The distribution of STS increased with age according to SEER data from 2001 to 2005. Of all STS cases, 10.3% were in children and young adults less than 20 years of age (NCI 2008a). The median age at diagnosis of STS, including tumors of the heart, was 57 years (NCI 2008b).

Staging

Disease progression may be dichotomized into the two categories of limited and extensive disease. Limited disease is typically a localized, small-sized, low-grade and operable and accessible tumor that has no regional lymph node involvement and no distant metastases. Extensive disease can also be denoted as advanced disease, defined as localized, large-sized and high-grade tumor that may not be completely removed by surgery, may be invasive and may have regional lymph node involvement or distant metastases. Both categories differ significantly in terms of prognosis and treatment. Where many patients with limited disease may be cured by surgery, extensive disease is associated with a poor outcome and many patients receive chemotherapy as palliative therapy.

The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system combines grade, depth and size of the tumor as well as regional lymph node involvement and distant metastases and describes the extent of a cancer's spread from stage 0 to IV (AJCC 2002). A review reported the five-year overall survival (OS) estimates for stage I (low-grade, superficial and deep), II (high-grade, superficial and deep), III (high-grade, large and deep) and IV (any metastasis to lymph nodes or distant sites) as approximately 90%, 70%, 50% and 10% to 20%, respectively; information on treatment was not given (Clark 2005). A multicenter study a total of 2185 participants with advanced STS revealed a median survival of 12 months (Van Glabbeke 1999). In the same study, of the 1922 (26%) eligible participants who responded to chemotherapy the five-year OS was 10%; in univariate analyses the response to chemotherapy was not predicted by the same factors as was OS.

Symptoms

The location of the primary tumor can involve any area of the body. The distribution is 40% lower limb and girdle, 20% upper limb and girdle, 20% abdominal sites, 10% trunk and 10% head and neck (Clark 2005). NRSTS can involve any type of tissue and typically affect muscles, tendons, adipose tissue, blood vessels and joints (Sondak 2001) and commonly present as a painless mass. The symptoms depend on the anatomical site of origin, the size of the mass and other aspects. Retroperitoneal sarcomas are most often asymptomatic, until the mass grows large enough to be clinically obvious or presses on vital organs and causes pain (Dileo 2005).

Patients who relapse or suffer progressive disease after therapy or metastasis are commonly called high-risk patients because these signs are associated with shorter survival time. Spontaneous recovery from NRSTS is unknown.

Description of the intervention

Standard therapy

Surgery is the standard treatment for localized NRSTS (ESMO 2012) and can be curative if distant dissemination is not present (Kotilingam 2006). Chemotherapy is a standard treatment for patients with distant metastasis (ESMO 2012) and is regarded mainly as a palliative treatment for high-risk patients who are characterized by inoperable, locally advanced and metastatic disease. Doxorubicin, ifosfamide, gemcitabine, dacarbacine, docetaxel and trabectedin are used in monotherapy or in combinations (ESMO 2012). Riedel 2012 provides an overview of current systemic therapies and discusses possible novel therapeutic agents and treatment strategies.

High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT)

Autologous hematopoietic stem cell transplantation (HSCT) is defined as the transplantation of stem cells that have been collected previously from bone marrow or peripheral blood of the same person. High-dose chemotherapy (HDCT) uses higher doses of chemotherapeutic agents than are usually applied in standard-dose chemotherapy. HDCT may be tolerated by the patient or it may ablate the patient's bone marrow reserves and create an absolute requirement for stem cell rescue. Instead of HDCT, high-dose radiation therapy may be used to treat NRSTS patients. Autologous HSCT applied after HDCT or high-dose radiation is a planned rescue therapy for HDCT-related severe hematologic toxicity (Banna 2007). Ideally, a mega-therapy regimen should be used consisting of several non-cross resistant agents that have a steep dose-response curve and little extramedullary toxicity (Ladenstein 1997).

HDCT and autologous HSCT are not standard treatment options; they are an experimental approach mainly used to treat high-risk people with an unfavorable prognosis (stage IV with distant metastases). HDCT and autologous HSCT may be used in special cases after careful consideration, usually for patients who respond well to standard chemotherapy according to Response Evalauation Criteria in Solid Tumors (RECIST) (Therasse 2000) criteria (Kasper 2005; Kasper 2007b). Carboplatin, cisplatin, cyclophosphamide, etoposide, ifosfamide, melphalan, mitoxantrone and thiotepa, for example, have been used in HDCT regimens. Independent of the disease status, HDCT and autologous HSCT are hazardous interventions that carry the risk of life-threatening organ failure.

Adverse events

Non-hematological adverse events, such as short-term and long-term organ toxicities, must be considered when using HDCT (Ladenstein 1997). Hematological adverse events as a result of autologous HSCT are usually manageable but life-threatening consequences of pancytopenia. They generally affect all patients and include, for example, graft failure, severe infections and bleeding.

Frequency

Of a total of 20,017 autologous HSCTs that were registered in Europe in the year 2010, by the European Group for Blood and Marrow Transplantation (EBMT), 45 were indicated for STS (Passweg 2012).

How the intervention might work

HDCT followed by autologous HSCT was adopted to treat high-risk patients because it was believed that escalating doses in chemotherapy might increase survival by capturing putatively remnant malignant cells and might overcome resistance to standard-dose chemotherapy (Banna 2007). High-dose chemotherapy may cause severe hematologic and non-hematologic toxicity and autologous HSCT is a planned rescue therapy for the HDCT-related demise of hematopoietic stem cells.

Why it is important to do this review

In the last two decades, from 1986 to 2007, the lack of evidence and need to conduct randomized controlled trials (RCTs) was stated by authors seeking to clarify the relevance of HDCT followed by autologous HSCT in high-risk patients with STS (Blay 2000; Carvajal 2005; Dumontet 1992; Ek 2006; Elias 1998; Kasper 2007a; Ladenstein 1997; Pinkerton 1986; Reichardt 2002; Rosti 2002; Schlemmer 2006; Seeger 1991; Woods 1999). Some authors have warned against the use of HDCT followed by autologous HSCT, indicating the possibility of repositioning of malignant cells (Woods 1999). Others have questioned the use of HDCT with reference to the potential existence of refractory cancer stem cells (Banna 2007; Bonnet 1997; Sanchez-Garcia 2007). The rationale for this review update is to review the latest available evidence and to clarify whether RCTs have been conducted and whether results of any study show evidence of a survival advantage.

Objectives

To assess the effectiveness and safety of high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HDCT) for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults.

Methods

Criteria for considering studies for this review

Types of studies

Inclusion criteria
  • Randomized controlled trials (RCTs).

Since we expected to find few if any RCTs, non-RCTs were also included as follows.

  • Prospective non-randomized controlled trials (denoted quasi-RCTs in the first version), other non-RCTs such as prospective and retrospective cohort studies, case-control studies, phase I and II prospective studies, case series and case reports.

Results from RCTs and controlled clinical trials (CCTs) may provide data for estimation of effects on overall survival (OS) and answer the question: does the intervention provide a significantly better survival than the control and does the quality of the studies fit with the assumption that the intervention is better than the control? Data from non-comparative studies (phase I and II prospective studies, case series and case reports) were collected to estimate treatment-related mortality (TRM) within a cohort of participants. Due to the lack of a control group these studies do not provide data for estimation of treatment effect.

Exclusion criteria

None

Rationale for including non-RCTs

Authors of studies on HDCT with autologous HSCT have stated that RCTs are both necessary and feasible. However, NRSTS is a rare disease and, according to the results of a previous literature search, currently there are no published RCTs available. In addition, CCTs or studies with any comparative data may be unlikely or rare. If they do exist they may be of low methodological quality. Based on the assumption that it is unlikely that the intervention has been or will be studied in RCTs in the near future, this systematic report of the findings and the limitations of all available published studies will be useful, for example for informing the design of appropriate RCTs and providing a summary of all of the evidence on the topic to date.

Types of participants

Inclusion criteria

We have adopted the World Health Organization (WHO) classification of soft tissue tumors to define the population of patients with NRSTS (Fletcher 2002) with the exception of the Ewing family of tumors (see 'Exclusion criteria' below). Studies were included as long as at least 80% of patients had NRSTS. Children as well as adults were investigated and age limits did not apply. Participants were included regardless of the severity of the disease and the clinical staging information, as long as they received autologous (from either a peripheral or bone marrow source, or both) HSCT.

Exclusion criteria

Whilst the WHO classification of NRSTS includes the Ewing family of tumors, that is extraosseous tumor types, we excluded these types because they are primarily bone sarcomas. Because extraosseous types are rarely diagnosed and share common features, they were regarded as one entity with osseous types and were excluded.

The clear delineation of soft tissue sarcomas to be included in the present report and the grounds for exclusion of some tumor types was hindered by the presence of more than 30 heterogenous tumor entities, the distinction between malignant tumors and two categories of intermediate malignancies as described in the WHO classification (Fletcher 2002), and a complicated histology and terminology. Therefore, we present the designation of tumors that were regarded as (malignant) soft tissue sarcomas in the present review (Table 2) and we present the terms for tumors that were not considered (Table 3).

Table 2. Included non-rhabdomyosarcoma soft tissue sarcomas (NRSTS)
  1. * category of malignant tumors according to the World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone (Fletcher 2002)

Diagnosis(*)
Alveolar soft part sarcoma
Anaplastic soft tissue sarcoma

Angiosarcoma

  1. Angiosarcoma of soft tissue

  2. Hemangiosarcoma

  3. Hemangiopericytoma

  4. Lymphangiosarcoma

Clear cell myomelanocytic tumor
Clear cell sarcoma of soft tissue
Desmoplastic small round cell tumor
Epithelioid sarcoma

Fibrosarcoma

  1. Adult fibrosarcoma

  2. Myxofibrosarcoma

  3. Low grade fibromyxoid sarcoma; hyalinizing spindle cell tumor

  4. Sclerosing epithelioid fibrosarcoma

Fibromyxoid sarcoma
Epithelioid hemangioendothelioma
Intimal sarcoma

Leiomyosarcoma

  1. Leiomyosarcoma (excluding skin)

Liposarcoma

  1. Dedifferentiated liposarcoma

  2. Myxoid liposarcoma

  3. Round cell liposarcoma

  4. Pleomorphic liposarcoma

  5. Mixed-type liposarcoma

  6. Liposarcoma, not otherwise specified (added by authors: chondroid liposarcoma)

Malignant fibrous histiocytoma

  1. Pleomorphic malignant fibrous histiocytoma; undifferentiated pleomorphic sarcoma

  2. Giant cell malignant fibrous histiocytoma; undifferentiated pleomorphic sarcoma with giant cells

  3. Inflammatory malignant fibrous histiocytoma; undifferentiated pleomorphic sarcoma with prominent inflammation

  4. Undifferentiated pleomorphic sarcoma

  5. Spindle cell sarcoma

Malignant glomus tumor
Malignant haemangiopericytoma
Malignant mesenchymoma
Mesenchymal sarcoma
Neoplasms with perivascular epithelioid cell differentiation (PEComa)

Rhabdoid sarcoma

  1. Extra-renal rhabdoid tumor

  2. Extra-cerebral rhabdoid tumor

Synovial sarcoma
Table 3. Excluded tumor types
  1. * WHO: World Health Organization

DiagnosisReason for exclusion(*)
Atypical teratoid/rhabdoid tumorsWHO classification of tumors of the central nervous system

Chondrosarcoma

  1. Mesenchymal chondrosarcoma

  2. Extraskeletal myxoid chondrosarcoma ('chordoid type')

Extraskeletal types are difficult to separate
Clear cell sarcoma of the kidneyExcluded by the authors of the present review
Dermatofibrosarcoma protuberansWHO classification of tumors of the skin
Endometrial stroma sarcomaWHO classification of tumors: pathology and genetics of tumors of the breast and female genital organs

Ewing family of tumors

  1. Ewing sarcoma

  2. Skeletal Ewing's sarcoma

  3. Extraskeletal Ewingsarcoma

  4. Peripheral primitive neuroectodermal tumour (pPNET)

  5. Extraskeletal peripheral primitive neuroectodermal tumor (pPNET)

  6. Askin tumor

Extraskeletal types are difficult to separate; the Ewing family of tumors is one entity
Extragonadal germ cell sarcoma

WHO classification of tumors: pathology and genetics of tumors of the urinary system and male genital organs

WHO classification of tumors: pathology and genetics of tumors of the breast and female genital organs

Follicular dendritic cell sarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
GanglioneuroblastomaWHO classification of nervous system tumors
Gastrointestinal stromal tumorWHO classification of tumors: pathology and genetics of tumors of the digestive system
Giant cell fibroblastomaWHO classification of tumors of the skin
Giant cell tumour of boneWHO classification for tumors of bone tissue
Histiocytic sarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
Interdigitating dendritic cell sarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
Interdigitating reticulum cell sarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
Kaposi sarcomaIntermediate malignancy (rarely metastasizing)
Lymphoblastic lymphosarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
Malignant ectomesenchymomaExcluded by the authors of the present review
MedulloblastomaWHO classification of tumors of the central nervous system
Myeloid sarcomaWHO classification of tumors of hematopoietic and lymphoid tissues
Myxosarcoma (cardiac tumor)WHO classification of tumors: pathology and genetics of tumors of the lung, pleura, thymus and heart
NephroblastomaWHO classification of tumors: pathology and genetics of tumors of the urinary system and male genital organs
Neuroblastoma (Wilms tumor)WHO classification of tumors: pathology and genetics of tumors of the urinary system and male genital organs

Osteosarcoma

  1. Extraskeletal osteosarcoma

Extraskeletal types are difficult to separate
ParagangliomaWHO classification of nervous system tumors
Peripheral nerve sheath tumor, malignant (neurofibrosarcoma)WHO classification of nervous system tumors
Rhabdoid tumor, renalWHO classification of tumors: pathology and genetics of tumors of the urinary system and male genital organs
Rhabdoid tumor, cerebralWHO classification of tumors of the central nervous system

Rhabdomyosarcoma

  1. Embryonal rhabdomyosarcoma (including spindle cell, botryoid, anaplastic)

  2. Alveolar rhabdomyosarcoma (including solid, anaplastic)

  3. Pleomorphic rhabdomyosarcoma

  4. Undifferentiated rhabdomyosarcoma

A soft tissue sarcoma that is excluded to separate rhabdomyosarcomas from non-rhabdomyosarcoma soft tissue sarcomas
Schwannoma, malignant (Schwannosarcoma)WHO classification of nervous system tumors
Stromal cell sarcomaNot part of the WHO classification of soft tissue sarcomas, malignant tumors
Unclassified sarcomaIt is not clear that the tumor is a non-rhabdomyosarcoma soft tissue sarcoma
Undifferentiated sarcomaIt is not clear that the tumor is a non-rhabdomyosarcoma soft tissue sarcoma
Uterine endometrial stromal sarcomaWHO classification of tumors: pathology and genetics of tumors of the breast and female genital organs

Types of interventions

Intervention: autologous hematopoietic stem cell transplantation (HSCT), stem cells from a peripheral source or the bone marrow, serving as a rescue therapy usually applied after high-dose chemotherapy (HDCT).

Comparison: standard-dose chemotherapy, which is defined as chemotherapy at a lower dose than HDCT without the need for stem cell rescue.

Types of outcome measures

Primary outcomes
  • Overall survival (OS): the event was death by any cause, from diagnosis or start of HDCT and autologous HSCT.

  • Treatment-related mortality (TRM): incidence of deaths that were classified as treatment related or the participants died of treatment complications.

Secondary outcomes
  • Disease-free survival (DFS): time free of disease after diagnosis or start of HDCT and autologous HSCT. We provided the definitions reported in the studies.

  • Progression-free survival (PFS): time staying free of disease progression after diagnosis or start of HDCT and autologous HSCT. We provided the definitions reported in the studies.

  • Event-free survival (EFS): time staying free of any of a particular group of defined events after diagnosis or start of HDCT and autologous HSCT. We provided the definitions reported in the studies.

  • Non-hematological toxicity grade 3 to 4: adverse events classified according to the common toxicity criteria (NCI 2009b) within 90 days of start of HDCT and autologous HSCT; grades 3 and 4 of toxicity were extracted for non-hematological (nausea, mucositis, kidney, liver, nervous system, heart, other) toxicities.

  • Secondary neoplasia: as classified by the study authors.

  • Health-related quality of life measured by validated questionnaires.

Search methods for identification of studies

Electronic searches

We conducted an electronic database search of MEDLINE (Ovid), including articles published between 1946 and 5 December 2012, by using the search strategy shown in Appendix 1. We searched EMBASE (Ovid), including articles published between 1980 and 5 December 2012, by using the search strategy shown in Appendix 2. We searched The Cochrane Library, including articles published from inception to 5 December 2012, by using the search strategy shown in Appendix 3. The original strategies which were run on 5 February 2010 and are shown in Appendix 4 for MEDLINE (Ovid), in Appendix 5 for EMBASE (Ovid), and in Appendix 6 for The Cochrane Library. For this update we considered all studies that were included in the original review and re-evaluated them.

We searched for ongoing trials by scanning the online registries ClinicalTrials.gov (ClinicalTrials.gov 2012) and the World Health Organization International Clinical Trials Registry Platform (ICTRP 2012) on 5 December 2012 for additional completed or ongoing studies using the search strategy "sarcoma AND chemotherapy AND transplantation". For the update of the present review we searched abstracts of annual meetings of the following societies via EMBASE (Ovid): American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), Bone Marrow Transplantation (BMT) Tandem Meeting of the American Society for Blood and Marrow Transplantation (ASBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR), and European Group for Blood and Marrow Transplantation (EBMT).

The search strategies used have been developed and executed by the author team.

Searching other resources

We located information about trials not registered in electronic databases by searching the reference lists of relevant articles and review articles such as Banna 2007, Ek 2006, Pedrazzoli 2006, and Verma 2008a. For the update, we did not identify more recent reviews. We contacted authors to replenish missing information.

Data collection and analysis

Selection of studies

We endorsed the PRISMA statement, adhered to its principles and conformed to its checklist (Moher 2009). We re-ran the whole selection process including all records retrieved from the inception of each database. We retrieved all titles and abstracts by electronic searching and downloaded them to the reference management database EndNote Version X3 (Thomson Reuters Corp 2012). We removed duplicates and two review authors examined the remaining references independently (FP, CB). We excluded those studies that clearly did not meet the inclusion criteria and we obtained copies of the full texts of potentially relevant references. Two authors (FP, CB) assessed the eligibility of retrieved papers independently. We resolved disagreement by discussion and it was not necessary to consult a third review author. We considered studies written in languages other than English and asked peers familiar with the particular language and with the principles of study evaluation to translate major methodological issues. We also used the Google Translate 2012 program. We documented reasons for the exclusion of studies.

Data extraction and management

We re-extracted the data from all selected studies identified from the inception of each database. Two review authors (FP, CB) independently abstracted data on study characteristics, patients and interventions, duration of follow up, outcomes, and deviations from the protocol. In addition, two review authors (FP, CB) independently assessed the risk of bias. We resolved differences between review authors by discussion or by appeal to a third review author (LS). All included studies were full-text publications.

We extracted the following data.

  • General information on author, title, source, publication date.

  • Study characteristics: trial design, setting, inclusion and exclusion criteria, comparability of patients' characteristics between groups, treatment allocation, blinding, subgroup analysis, length of follow-up.

  • Participant characteristics: age; gender; number of participants recruited, /allocated, affected, analyzed; additional diagnoses; participants lost to follow-up.

  • Interventions: type of high-dose chemotherapy, source of stem cells, and type of standard-dose chemotherapy.

  • Outcomes: overall survival, treatment-related mortality, disease-free survival, progression-free survival, event-free survival including type of event, toxicity, secondary neoplasia, health-related quality of life.

Assessment of risk of bias in included studies

Two review authors (FP, CB) independently assessed the risk of bias in the included studies using six criteria. We have used four criteria of The Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011a):

  1. random sequence generation (selection bias);

  2. allocation concealment (selection bias);

  3. blinding of outcome assessment (detection bias);

  4. selective reporting such as not reporting pre-specified outcomes (reporting bias).

We extended the tool for assessing risk of bias with five additional criteria that are specific for the inclusion criteria for the present review and that are critical for confidence in the results:

  1. prospective design;

  2. comparable baseline characteristics;

  3. assignment of patients to treatment groups;

  4. concurrent control;

  5. loss to follow-up.

We applied The Cochrane Collaboration's criteria for judging risk of bias (Higgins 2011b). In general, a 'low risk' of bias is judged if the bias is unlikely to seriously alter the results, for example, participants and investigators enrolling participants could not foresee assignment. A 'high risk' of bias is judged if the bias seriously weakens confidence in the results, for example, participants or investigators enrolling participants could possibly foresee assignments. 'Unclear' risk of bias is judged if the bias raises some doubt about the results, for example, the method of concealment is not described or not described in sufficient detail to allow a definite judgement.

We judged studies as prospective if an explicit statement was reported or there were clues suggesting a prospective design (for example prior approval of treatment, informed consent). We judged studies as retrospective if an explicit statement was reported or was implied by a description that data were reviewed from an existing source. We regarded each of the following items as an indication of a retrospective design: registry reports and reviewing of medical records.

Measures of treatment effect

The primary effect measure was the hazard ratio (HR) for time-to-event data. If the HR was not directly given in the publication, we planned to estimate HRs according to methods proposed by Parmar 1998 and Tierney 2007.

We planned to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes. In the case of rare events, we planned to use Peto odds ratio instead. We planned to analyze continuous data and to present them as mean differences, if all results were measured on the same scale (for example length of hospital stay). If this was not the case (for example pain or quality of life), we planned to use standardized mean differences.

Studies reporting aggregate data that combined the results of several participants (including results from separately reported subpopulations that fulfilled the inclusion criteria) were distinguished from studies with individual data of single participants. Data from these studies were described as narrative summaries. In some studies diagnoses of NRSTS were mixed with non-NRSTS solid tumors and rhabdomyosarcomas to such an extent that the proportion of NRSTS participants was less than 80% of the study population. In this case, if data on single participants were identified that fulfilled the inclusion criteria of the present review we included the study and data for the individual participant in our data analysis.

Estimates of OS were considered for the evaluation if the use of the Kaplan-Meier method was reported in the study. We described survival estimates from studies reporting aggregate data independent of the start of the follow-up period on the condition that these estimates were not pooled with those of other studies.

A survival analysis was conducted of individual participant level data based on the Kaplan-Meier method. Pooling required binary information on OS (0 = alive; 1 = dead) and on follow-up. In the majority of cases, the starting point of follow-up was the beginning of treatment. However, we accepted other starting points such as the time when the diagnosis or indication for treatment was established. Statistical analyses of time to event data were performed using SAS Version 9.2 (SAS Institute Corp 2012).

Unit of analysis issues

None

Dealing with missing data

We conformed to The Cochrane Collaboration's principal options for dealing with missing data and analysed only the available data (Higgins 2011c). If data were missing or only imputed data were reported we contacted trial authors to request data on the outcomes among participants who were assessed. We contacted the authors of the studies by Bui-Nguyen 2012, Ivanova 2010, Jordan 2010, Philippe-Chomette 2012, Schlemmer 2006 to ask for missing data about the histologic types that were combined as 'others'. The authors responded well and as a consequence we could base the inclusion or exclusion of patient data on the additional data.

Assessment of heterogeneity

We planned to assess heterogeneity between studies by visual inspection of forest plots; by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (I2 statistic) (Higgins 2003); by a formal statistical test of the significance of the heterogeneity (Cochran's Q) (Deeks 2011); and, if possible, by subgroup analyses (see 'Subgroup analysis and investigation of heterogeneity'). We planned to investigate and report possible reasons if there was evidence of substantial heterogeneity. We planned to use the random-effects model with inverse variance weighting for statistical pooling (DerSimonian 1986). We did not pool estimates.

Assessment of reporting biases

We conformed to The Cochrane Collaboration's criteria and planned to evaluate reporting biases such as publication bias, time lag bias, multiple (duplicate) publication bias, location bias, citation bias, language bias and outcome reporting bias (Sterne 2011). We did not assess reporting bias because of the low number of identified studies.

Data synthesis

One review author (FP) entered the data into Review Manager 2011. Another review author (CB) checked the entered data. Methods of synthesizing the studies depended on the quality, design and heterogeneity of the studies identified.

We planned to synthesize data on mortality (HDCT and autologous HSCT versus SDCT) by using the hazard ratio (HR) as effect measure in a random-effects model. However, data were too scarce to be reasonably pooled. Aggregate data were synthesized as narrative. In contrast, individual data were pooled and available time-to-event data were analyzed in a Kaplan-Meier survival analysis.

We used the software GRADEpro 3.2 (GRADEpro 2008) to create the 'Summary of findings' table 1 as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011).

Subgroup analysis and investigation of heterogeneity

We had planned subgroup analyses based on age, stage, and time period of treatment. However, we found no appropriate data to conduct these analyses.

Sensitivity analysis

We had planned sensitivity analyses to compare the results of studies with low versus high risk of bias. As all included studies had a high risk of bias, no sensitivity analyses were carried out.

Results

Description of studies

Clinical heterogeneity was substantial because tumor subdiagnosis varied considerable between patients. Furthermore, tumor stage was not reported for all participants. Study design was tenuously reported due to the identification of either aggregate data or individual patient data in one-arm studies. Overall, the likelihood of bias was very high except in the single randomized controlled trial (RCT). All studies were not comparable due to various subtypes.

Results of the search

For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. In the original review, we applied a search strategy that was designed to include all solid tumors including the Ewing family of tumors and rhabdomyosarcoma. This strategy resulted in the retrieval of a large number of documents (4782) including a very high fraction of not relevant retrieved documents. We revised the search strategy and this retrieved a considerably reduced number of retrieved documents (1035) from the inception of each electronic databases. The new strategy did not identify some single-arm studies with individual data that were included in the original review. Some individual cases are hidden in articles that do not mention soft tissue sarcomas and transplantation in the title or abstract. Some of those are missed by the new strategy. It is impossible to identify all published cases of transplanted patients with NRSTS. Therefore, the number of identified relevant cases will vary with different strategies. The retrieval information confirmed that the number of studies with comparative data and aggregate data did not vary and the number of these types of identified studies was robust. The new search strategy was more economical in terms of spending resources for study selection for the present review, and also for future updates. We did not ignore the results of the original review and re-evaluated all studies that were identified by the old strategy and were included in the original review.

We retrieved 1035 records applying the new search strategy. We also retrieved six ongoing studies. We imported 15 studies that were included in the original review but were not identified with the new search strategy. We screened 773 different articles after removal of duplicates (Figure 1). The titles and abstracts of 513 articles did not fulfil the inclusion criteria or they reported about ongoing studies. A total of 260 of the retrieved articles were evaluated in detail using the full text. Of these, a total of 62 records reporting about 57 studies were included in the present review and the other 198 references were excluded. We identified one randomized controlled trial (RCT), six single-arm studies with aggregate data, and 50 single-arm studies with individual data.

Figure 1.

Literature search and study flow.

Eight studies were published after the original retrieval and were added to the included studies (Bisogno 2010; Buerk 2010; Bui-Nguyen 2012; Cook 2012; Etienne-Mastroianni 2002; Houet 2010; Jordan 2010; Philippe-Chomette 2012). Nine further studies were included in the original review but were not identified by the new search strategy (Fang 2008; Graham 1997; Hawkins 2002; Kretschmar 1996; Krskova 2007; Matsuzaki 2002; Peters 1986; Peters 1989; Slease 1988) (Table 4). These 15 studies were included in the update in addition to the results of the new search strategy. Three studies were included in the original review and identified in the update but were excluded after re-evaluation (Ivanova 2010; Kaminski 2000; Kuehne 2000). Three studies were excluded in the original review and identified in the update but were included after re-evaluation (Blay 2000; Fetscher 1996; Mingo 2005). Six further studies were included in the original review and not identified in the update but were excluded after re-evaluation. Four studies reported about undifferentiated sarcoma, which is not included (Endo 1996; Frapier 1998; Mesia 1994; Nakamura 2008). One study reported about rhabdoid tumor but without information about the localisation, which is required for identification of the extrarenal and the extracerebral rhabdoid tumors (Ronghe 2004). One study reported on undifferentiated sarcoma and rhabdoid tumor without information about the localisation (Shaw 1996).

Table 4. Included studies identified by only one search strategy
  1. Eight studies were published after the original retrieval and were added to the included studies: Bisogno 2010; Buerk 2010; Bui-Nguyen 2012; Cook 2012; Etienne-Mastroianni 2002; Houet 2010; Jordan 2010; Philippe-Chomette 2012.

    Nine further studies were included in the original review but were not identified by the new search strategy: Fang 2008; Graham 1997; Hawkins 2002; Kretschmar 1996; Krskova 2007; Matsuzaki 2002; Peters 1986; Peters 1989; Slease 1988. These 15 studies were included in the update in addition to the results of the new search strategy.

    Three further studies were included in the original review and identified in the update but excluded after re-evaluation: Ivanova 2010; Kaminski 2000; Kuehne 2000.

    Three further studies were excluded in the original review and identified in the update but included after re-evaluation: Blay 2000; Fetscher 1996; Mingo 2005.

    Six further studies were included in the original review and not identified in the update but excluded after re-evaluation: Four studies reported about undifferentiated sarcoma, which is not included: Endo 1996; Frapier 1998; Mesia 1994; Nakamura 2008. One study reported about rhabdoid tumor but without information about the localisation, which is required for identification of the extra-renal and the extra-cerebral rhabdoid tumors: Ronghe 2004. One study reported about undifferentiated sarcoma and rhabdoid tumor without information about the localisation: Shaw 1996.

Old strategy (original)New strategy (update)
  Bisogno 2010
  Buerk 2010
  Bui-Nguyen 2012
  Cook 2012
  Etienne-Mastroianni 2002
Fang 2008 
Graham 1997 
Hawkins 2002 
  Houet 2010
  Jordan 2010
Kretschmar 1996 
Krskova 2007 
Matsuzaki 2002 
Peters 1986 
Peters 1989 
  Philippe-Chomette 2012
Slease 1988 

We retrieved a total of 49 studies in ClinicalTrials.gov 2012 and found 14 potentially relevant studies. We identified six ongoing studies, whereof two studies are currently recruiting (NCT00638898; NCT01288573) and four studies are not recruiting participants (NCT00002601; NCT00002854; NCT00141765; NCT00623077). We identified three completed studies, one terminated study that was withdrawn due to slow accrual, and four studies with unknown status and information that has not been verified recently. The investigators did not provide results via the registry and we did not found a publication in PubMed 2012 matching the data shown in the registry. Of the rest of the 35 studies, 15 studies did not include the diagnosis of interest, 15 studies did not include the intervention of interest, and five did not include the outcome of interest. We did not identify other relevant studies searching in the two trials registries ICTRP 2012 and ISRCTN 2012. We did not identify any additional studies from screening the reference lists of included studies and reviews.

Included studies

We identified 57 studies including a total of 275 participants that received HDCT and autologous HSCT. The characteristics of all 57 included studies are described in the section Characteristics of included studies. We have provided a tabulated overview of seminal characteristics in Table 5.

Table 5. Overview of included studies
  1. (*) modified ITT: histologically ineligible patients excluded from primary group of analysis; HDCT group: 3 of 41 randomized data excluded; SDCT group: 1 of 46 randomized data excluded

    Abbreviations: Diag: diagnosis; HDCT: high-dose chemotherapy (& autologous hematopoietic stem cell transplantation); HR: hazard ratio; HSCT: hematopoietic stem cell transplantation; ITT: intention to treat; N: number of participants; Nspe: not specified; Prosp: prospective study design; Rand: randomization Rel: relevant; SDCT: standard-dose chemotherapy; Ther: therapy; vs.: versus

    Diagnoses: ANA: anaplastic soft tissue sarcoma; ANG: angiosarcoma; CCS: clear cell sarcoma; DSRCT: desmoplastic small round-cell tumor; EPI: epitheloid sarcoma; FIB: fibrosarcoma; FMS: fibromyxoid sarcoma; HAP: hemangiopericytoma; LIP: liposarcoma; LMS: leiomyosarcoma; MES: mesenchymal sarcoma; MFH: malignant fibrous histiocytoma; MHP: malignant hemangioperiocytoma; MME: malignant myoepithelioma; NRSTS: various types of non-rhabdomyosarcoma soft tissues sarcomas; RHA: rhabdoid tumor; SCS: spindle cell sarcoma; SYN: synovial sarcoma; UCS: unclassified sarcoma; UDS: undifferentiated sarcoma

StudyTotal, NDiagnosisStart of follow upProspectiveHDCT vs. SDCT, N analyzed
Not rel, N (%)Rel, NAffected patients, N; type of included diagnosis
Aggregate comparative data (HDCT & autologous HSCT vs. SDCT)
Bui-Nguyen 20128718 (20)6916x LMS, 16x MFH, 10x LPS, 9x SYN, 6x ANG, 2x UDS, 2x MME, 2x DSRCT, 2x FIB, 1x LMS, 1x UCS, 1x CCSRandomizationYES38 vs. 45 in ITT(*)
Subtotal comparative data in 1 study 38 vs. 45
Aggregate case series data (HDCT & autologous HSCT only)
Bertuzzi 2003100 (0)1010x DSRCTTherapyYES10
Bisogno 2010140 (0)1414x DSRCTDiagnosisYES14
Blay 2000242 (10)2224x NRSTSTherapyYES24
Bokemeyer 1997182 (11)165x MFH, 4x HAP, 3x SYN, 2x LMS, 2x MESTherapyno16
Cook 2012360 (0)3636x DSRCTTherapyno36
Philippe-Chomettte 2012140 (0)1414x DSRCTDiagnosisno14
Subtotal case series in 6 studies 114
Individual cases data (HDCT & autologous HSCT only)
Al Balushi 20093  3x DSRCT no3
Andres 20061  1x DSRCT no1
Bernbeck 20072  2x SYN no2
Bley 20041  1x LIP no1
Boelke 20051  1x MFH no1
Buerk 20101  1x MFH no1
Cole 19991  1x SYN no1
Doros 20081  1x DSRCT no1
Engelhardt 200735  ANA, ANG, FIB, LMS, LIP, MFH, MHP, SYN no23
Etienne-Mastroianni 200212  1x LMS no1
Fang 20082  1x DSRCT no1
Farruggia 20081  1x SYN no1
Fetscher 19961  1x LMS no1
Fetscher 19971  1x LMS no1
Fraser 200636  4x DSRCT YES4
Garrido 19982  1x LIP no1
Graham 199749  1x FIB YES1
Hara 20101  1x ANG no1
Hawkins 200223  2x DSRCT, 1x FMS, 1x LMS YES6
Hoogerbrugge 19971  1x FIB no1
Houet 20101  1x DSRCT no1
Jordan 201016  2x EPI, 1x SYN, 1x SCS, 1x LMS, 1x ANG, 1x HAP YES7
Kasper 2007a38  5x SYN, 3x LMS, 2x LIP 1x MFH no11
Kasper 20109  2x MFH, 1x LMS, 1x SYN YES4
Kozuka 20022  1x MFH, 1x MHP no2
Kretschmar 19963  1x DSRCT no1
Krskova 20071  1x SYN no1
Kurre 20002  2x DSRCT no2
Kushner 199612  4x DSRCT YES4
Kushner 200121  1x DSRCT YES1
Kushner 20081  1x DSRCT no1
Lafay-Cousin 200018  2x DSRCT YES2
Lashkari 200913  1x MFH YES1
Lippe 20032  1x DSRCT no1
Livaditi 20065  2x DSRCT no2
Madigan 200714  1x RHA no1
Matsuzaki 20021  1x SYN no1
Mazuryk 19981  1x DSRCT no1
Mingo 20051  1x DSRCT no1
Mitchell 199411  1x ANG no1
Navid 200624  2x DSRCT no2
Patel 200437  6x MFH YES6
Peters 198629  1x FIB, 1x LMS YES2
Peters 198923  2x SYN YES2
Recchia 20061  1x MFH no1
Saab 20074  4x DSCRT no4
Slease 198826  2x MFH, 1x LMS no3
Sung 200326  1x CCS, 1x MFH no2
Yamamura 20031  1x MFH no1
Yonemoto 199910  3x SYN no3
Subtotal individual cases in 50 studies 123
Summary of patient count 
Subtotal HDCT & autologous HSCT in 57 studies 275
Subtotal SDCT in 1 study45
Total in 57 studies 320
Design

We included one RCT with two parallel treatment groups, HDCT and autologous HSCT versus SDCT (Bui-Nguyen 2012). It was an open, multicenter, randomized phase III study. All patients received the same baseline treatment. Patients were eligible for randomization if they had responded to chemotherapy or, for stable disease, if a complete surgical resection of all disease sites could be carried out. Randomization was carried out centrally. The intention-to-treat (ITT) modified population included all randomly assigned patients excluding patients found to be ineligible at central histology review.

We included six single-arm studies that reported aggregate data of participants that received HDCT and autologous HSCT and that consisted of at least 80% with relevant NRSTS (Bertuzzi 2003; Bisogno 2010; Blay 2000; Bokemeyer 1997; Cook 2012; Philippe-Chomette 2012). Three of the studies collected the data prospectively (Bertuzzi 2003; Bisogno 2010; Blay 2000) and three retrospectively (Bokemeyer 1997; Cook 2012; Philippe-Chomette 2012). The remaining 50 studies comprised single-arm studies without appropriate aggregate data. Relevant participants were considered in the survival analysis of pooled individual data.

Sample sizes

The authors of the RCT (Bui-Nguyen 2012) conducted an ITT analysis of 38 participants in the HDCT arm versus 41 participants in the SDCT arm. Six single-arm studies reported aggregate data of 10 (Bertuzzi 2003), 14 (Bisogno 2010), 24 (Blay 2000), 16 (Bokemeyer 1997), 36 (Cook 2012), and 14 (Philippe-Chomette 2012) participants with NRSTS who received HDCT and autologous HSCT. Fifty studies reported on 123 individual relevant participants. Overall survival and follow-up data were reported for 80 participants in 41 studies and subsequently those data could be considered in survival analysis of the pooled individual data.

Setting

The 57 studies were set in 12 different countries, eight countries in Europe (Czech Republic, France, Germany, Greece, Italy, Netherlands, Spain, United Kingdom), two in North America (Canada, United States), and two in Asia (Korea, Japan). Most of the transplanted patients were studied in the USA (79 of 260) and France (79 of 260). In four countries (France, Germany, Italy, USA) 10 or more patients were studied. The only RCT (Bui-Nguyen 2012) was set in France.

Participants

We included 275 patients with 15 different relevant histological diagnoses in 57 studies. Most patients (N = 109) had desmoplastic small round-cell tumor; 10 or more patients were reported for angiosarcoma, desmoplastic small round-cell tumor, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, and synovial sarcoma.

Bui-Nguyen 2012 reported the age in the HDCT arm in a range of 18.5 to 65.0 years (median 45.8 years) and a comparable age in the SDCT arm with a range of 18.7 to 65.0 years (median 43.3 years). Males were 58.5% of participants (24 of 41) in the HDCT arm and 50% (23 of 46) in the CDCT arm.

Bertuzzi 2003 reported a range of 15 to 60 years of age (median 29 years) for the 10 male patients that were included. Bisogno 2010 included 13 males and one female, the age range was 2 to 17.8 years (median 10.3 years). Blay 2000 reported on 30 patients of which 17 were males and 13 females. The age ranged from 17 to 57 years (median 34 years). Bokemeyer 1997 reported the age range between 25 and 57 years with a median of 45 years. Gender was not specified. Cook 2012 reported the age range between 8 and 46 years with a median of 19 years; 29 were males and 7 were females. Philippe-Chomette 2012 reported an age range of 4 to 22.6 years for 14 transplanted patients in the HDCT arm; 12 of those patients were males and 2 females.

Age was provided for 113 of 123 individual patients ranging from 1 to 65 years with a median of 27 years. Gender was provided for 83 individual patients, of which 55 were male and 28 were female. Follow-up was provided for 80 individual patients, ranging from 0 to 120 months with a median of 17 months.

Interventions

Components and the dosage of various chemotherapeutic regimens are described in the Characteristics of included studies.

In the study by Bui-Nguyen 2012, 87 patients received courses one to five of standard-dose chemotherapy. Forty-one patients were randomized to receive HDCT and transplantation of autologous peripheral stem cells as course six in the HDCT arm. Of these, 38 patients were analyzed in a modified ITT analysis. Forty-six patients were randomized to again receive standard-dose chemotherapy as course six. Of these, 45 patients were analyzed in a modified ITT analysis.

In the study by Bertuzzi 2003, after a four-course induction phase 10 patients in complete or partial response received HDCT and autologous HSCT using peripheral blood as the stem cell source. In the study by Bisogno 2010, after an induction phase of nine weeks 14 patients at various clinical stages received three consecutive intensified-dose combinations and autologous HSCT using peripheral blood as the stem cell source. In the study by Blay 2000, after induction chemotherapy for most of the patients 24 patients with an advanced clinical stage including 87% with metastasis received HDCT and autologous HSCT. The stem cell source was mainly bone marrow (N = 25) and a few patients received stem cells from peripheral blood (N = 5). In the study by Bokemeyer 1997, 16 patients received HDCT and autologous HSCT from peripheral blood. In the study by Cook 2012, 36 patients received HDCT and autologous HSCT mainly from peripheral blood (N = 33) and a few from bone marrow (N = 2), with information missing in one patient. In the study by Philippe-Chomette 2012, 14 patients received various regimens of HDCT and autologous HSCT. The source of stem cells was not reported.

Primary outcome

All seven included studies with aggregate data (Bertuzzi 2003; Bisogno 2010; Blay 2000; Bokemeyer 1997; Bui-Nguyen 2012; Cook 2012; Philippe-Chomette 2012) reported overall survival (OS). Among the 50 studies with individual data from 123 patients, OS and follow-up were reported for 80 patients. Ten studies reported treatment-related mortality (TRM), five of seven studies with aggregate data and five of 50 studies with individual data. There were 13 events in nine and zero events in one study.

Secondary outcomes

One study reported disease-free survival, five studies reported progression-free survival, nine reported non-hematological toxicity grade 3 to 4, and one study reported secondary neoplasia. Five studies reported on five severe adverse events.

Excluded studies

A total of 198 references of the potentially relevant articles were excluded (Figure 1) based on:

  • not diagnosis of interest, NRSTS according to Table 2 or relevant data not reported separately (n = 95);

  • not intervention of interest, not HDCT and autologous HSCT (n = 69);

  • not outcome of interest or not reported separately (n = 2);

  • not publication type of interest, a review, editorial, letter, duplicate data, or congress abstract (n = 32).

Excluded studies are described in the Characteristics of excluded studies table.

Risk of bias in included studies

We have identified one comparative study with a randomized design (Bui-Nguyen 2012). We think that this trial stands out and has substantially less risk of bias than the rest of the studies. Fifty-six of 57 studies were single-arm studies that subsequently had a very high risk of bias, see Characteristics of included studies. An overview of the risk of bias is shown in Figure 2 and the risk of bias for each study is shown in Figure 3.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We have identified true randomization including highly probable adequate random sequence generation for Bui-Nguyen 2012 and judged a low risk of bias for this study. We judged a high risk of bias for the rest of the studies.

Assignment of patients to treatment groups

In the study by Bui-Nguyen 2012, patients were assigned to two different treatment arms in a randomized fashion. Thus we judged a low risk of bias for this study. The rest of the studies were single-arm studies with an observational design and we judged a high risk of bias for these studies.

Blinding

Blinding of outcome assessment was not addressed in all included studies. Thus, we judged a high risk of bias for all studies.

Incomplete outcome data

Bui-Nguyen 2012 conducted a modified ITT analysis. The exclusion of histologically ineligible patients after randomization affected three of 41 patients in the HDCT arm and one of 46 patients in the SDCT arm. All other studies analyzed the patients as treated. Thus we judged a low risk of bias for Bui-Nguyen 2012 and a high risk of bias for the rest.

Selective reporting

In the study by Bui-Nguyen 2012, allocation was carried out centrally, though masking of allocation was not described in full detail. Thus we judged an unclear risk of bias for this study. We judged a high risk of bias for the rest of the studies.

Other potential sources of bias

Prospective design

The one RCT was prospective (Bui-Nguyen 2012), three of the six single-arm studies with aggregate data (Bertuzzi 2003; Bisogno 2010; Blay 2000) and 12 of the 50 single-arm studies with individual data (Fraser 2006; Graham 1997; Hawkins 2002; Jordan 2010; Kasper 2010; Kushner 1996; Kushner 2001; Lafay-Cousin 2000; Lashkari 2009; Patel 2004; Peters 1986; Peters 1989) had prospective parts. The prospective design may be advantageous for studies that present aggregate data from a series of patients treated in a certain time period. The prospective design is not relevant for individual data. Thus, we judged a low risk of bias for Bui-Nguyen 2012, Bertuzzi 2003, Bisogno 2010, and Blay 2000 and we judged a high risk of bias for the rest.

Comparable baseline characteristics

Bui-Nguyen 2012 had a randomized controlled design and the baseline characteristics of both treatment groups were comparable. Thus, we judged a low risk of bias for Bui-Nguyen 2012 and a high risk of bias for the rest.

Concurrent control

We identified a concurrent control group in Bui-Nguyen 2012 and judged a low risk of bias. The rest of the studies did not report a control group and we judged a high risk of bias. Note: Philippe-Chomette 2012 reported the results of some cases with conventional chemotherapy. The data for those cases were probably observed and not part of an experimental design, collected retrospectively in different time periods.

Loss to follow-up

Bui-Nguyen 2012 conducted a modified ITT analysis. The exclusion of histologically ineligible patients after randomization affected three of 41 patients in the HDCT arm and one of 46 patients in the SDCT arm. All other studies analyzed the participants as treated. Thus we judged a low risk of bias for Bui-Nguyen 2012 and a high risk of bias for the rest.

Effects of interventions

See: Summary of findings for the main comparison Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcoma

Primary outcome

Overall survival

Overall survival (OS) was not statistically significantly different between HDCT and autologous HSCT versus SDCT at three years in the RCT by Bui-Nguyen 2012: 32.7% versus 49.4% with a HR of 1.26 (95% CI 0.70 to 2.29, P = 0.44) (Table 6). The authors separately analyzed patients that had achieved a complete response to induction therapy before HDCT. OS was higher in the complete response patients compared to all patients and OS was statistically significantly different between the treatment arms. The OS among the patients that have achieved a complete response at three years before HDCT was 42.8% versus 83.9% with a HR of 2.92 (1.1 to 7.6, P = 0.028) (Table 6).

Table 6. Overall survival (OS)
  1. Some estimates were deduced from Kaplan-Meier plot.

    Bisogno 2010: 1 of 14 patients was reported to have achieved complete response before HDCT

    Blay 2000: all patients in subgroup N = 24, patients that achieved complete remission before HDCT N = 8, patients that did not achieve complete remission before HDCT N =16

    Bui-Nguyen 2012: all patients N = 38 vs. N = 45, patients that achieved complete remission before HDCT N = 20 vs. N 19

    Cook 2012: all patients N = 36, patients that achieved complete remission before HDCT N = 13, patients that did not achieve complete remission before HDCT N =18

    Abbreviation: CI: confidence interval; HDCT: high-dose chemotherapy; HR: hazard ratio; HSCT: hematopoietic stem cell transplantation; OS: overall survival; SDCT: standard-dose chemotherapy

StudyOS, % (95% CI)
All patients assessedComplete response before the time of HSCTNot complete response before the time of HSCT
Aggregate comparative data (HDCT & autologous HSCT vs. SDCT)
Bui-Nguyen 20123 years: 32.7% vs. 49.4%, HR 1.26 (0.70 to 2.29, P = 0.44)3 years: 42.8% vs. 83.9%, HR 2.92 (1.1 to 7.6, P = 0.028)Not reported
Aggregate case series data (HDCT & autologous HSCT only)
Bertuzzi 20032 years: 20%Not reportedNot reported
Bisogno 2010

2 years: 48%

3 years: 38.9%

Not reportedNot reported
Blay 2000Not reported

2 years: 62%

5 years: 62%

2 years: 27%

5 years: 5%

Bokemeyer 1997Median 13 months (range 3 to 19)Not reportedNot reported
Cook 20123 years: 40% (24 to 58)3 years: 57% (29 to 83)3 years: 28% (9 to 51)
Philippe-Chomettte 20122 years: 51.4% (23.2 to 79.6)Not reportedNot reported
Individual cases data (HDCT & autologous HSCT only)
50 studies

2 years: 50.6% (38.7 to 62.5)

3 years: 36.7 (24.4 to 49.0)

5 years: 29.9 (16.7 to 43.1)

Not reportedNot reported

The single-arm studies with aggregate data reported an OS at two years ranging from 20% to 51.4% and at three years ranging from 38.9% to 40% (Table 6). Blay 2000 and Cook 2012 compared patients that had achieved versus not achieved a complete response before HDCT. Blay 2000 reported an OS at two years of 63% versus 27%, and Cook 2012 reported an OS at three years of 57% versus 28% (Table 6). Again, the achievement of a complete response before HDCT was favorable with respect to OS. We conducted a survival analysis using individual data on the condition that survival status and time to event were reported. This was true for 65% (80 of 123) of the patient data; for 43 patients, follow-up data were not available. We estimated an OS at two years of 50.6% (95% CI 38.7 to 62.5) and at three years of 36.7% (95% CI 24.4 to 49.0) (Table 6). Both estimates were within the range of the other studies. We provided the OS for each individual case in Table 7. The graphical presentation of the Kaplan-Meier graph of all 80 included patients at risk is shown in Figure 4. We also analyzed the subgroup of patients with the diagnosis of desmoplastic small round-cell tumor because this diagnosis constituted the largest proportion, 34% (27 out of 80), of individual patients considered for the survival analysis (Figure 5). Of the individual data from patients with desmoplastic small round-cell tumor, 77% (27 of 35) had follow-up information. Both survival curves do not appear to be considerably different, though the median survival was 2.8 years within the subgroup of 27 patients with desmoplastic small round-cell tumor versus 2.2 years within the total population of 80 patients.

Figure 4.

Kaplan-Meyer analysis of overall survival of individual cases data from patient with various NRSTS

  • X-axis below line: years

  • X-axis above line: number of patients at risk

  • Y-axis: probability of overall survival

The Kaplan-Meyer analysis of overall survival was conducted using individual data of patients with NRSTS with available follow-up information (total 80, failed 46, censored 34) from 41 case series and case reports. Information about outcome (dead or alive) and follow-up (time of survival after diagnosis or begin of treatment) was required for each individual. Number of subjects at risk after each additional year of follow up.

Abbreviations: NRSTS: non-rhabdomyosarcoma soft tissue sarcoma

Figure 5.

Kaplan-Meyer analysis of overall survival of individual cases data from patient with DSRCT only

  • X-axis below line: years

  • X-axis above line: number of patients at risk

  • Y-axis: probability of overall survival

The Kaplan-Meyer analysis of overall survival was conducted using individual data of patients with NRSTS with available follow-up information (total 27, failed 13, censored 14) from case series and case reports. Information about outcome (dead or alive) and follow-up (time of survival after diagnosis or begin of treatment) was required for each individual. Number of subjects at risk after each additional year of follow up.

Abbreviations: DSRCT: desmoplastic small round cell tumor

Table 7. Overall survival: Individual cases data
  1. (*) Overall survival is dichotomized in alive (0) vs. dead (1) at follow up. Alive includes outcomes such as no evidence of disease, alive with disease, and alive with no further information about disease status. Dead includes outcomes such as died of diseasae, died of complications, and died with not further information of the cause of death. 45% (49 of 108) patients were reported as alive after a wide range of follow up time. This proportion remained 46% (33 of 71) after limiting to patients with follow up data.

    (**) Follow up was reported for 66% (71 of 108) patients and varied between 0 and 108 months after the period between diagnosis and beginning of HDCT. The time to event data of these 71 patients were used in a Kaplan Meier survival analysis. For 34% (37 of 108) patients, follow up was not reported and the data of those 37 patients could not be included in the survival analysis.

    Abbreviation: FU: follow-up; OS: overall survival

    Diagnoses: ANA: anaplastic soft tissue sarcoma; ANG: angiosarcoma; CCS: clear cell sarcoma; DSRCT: desmoplastic small round-cell tumor; EPI: epitheloid sarcoma; FIB: fibrosarcoma; HAP: hemangiopericytoma; LIP: liposarcoma; LMS: leiomyosarcoma; MES: mesenchymal sarcoma; MFH: malignant fibrous histiocytoma; MHP: malignant hemangioperiocytoma; RHA: rhabdoid sarcoma; SCS: spindle cell sarcoma; SYN: synovial sarcoma

StudyDiagnosis

Overall survival(*), 0 = alive,

1= dead

Follow up(**), months
Al Balushi 2009DSRCT072
DSRCT024
DSRCT018
Andres 2006DSRCT010
Bernbeck 2007SYN1 
 SYN0 
Bley 2004LPS07
Boelke 2005MFH089
Buerk 2010ANG01
Cole 1999SYN06
Doros 2008DSRCT10
Engelhardt 2007LPS0 
 LPS1 
 LPS0 
 ANA1 
 ANA1 
 ANA0 
 ANA0 
 ANA1 
 LMS0 
 LMS1 
 LMS1 
 LMS1 
 SYN0 
 SYN1 
 SYN1 
 SYN1 
 SYN1 
 MFH0 
 FIB1 
 FIB1 
 ANG0 
 ANG1 
 MHP1 
Etienne-Mastroianni 2002LMS078
Farruggia 2008SYN036
Fetscher 1996LMS0 
Fetscher 1997LMS036
Fraser 2006DSRCT0 
 DSRCT0 
 DSRCT0 
 DSRCT0 
Garrido 1998LPS0 
Hara 2010ANG167
Hoogerbrugge 1997FIB18
Houet 2010DSRCT0120
Jordan 2010SYN18
 MHP129
 ANG16
 EPI17
 EPI16
 LMS13
 SCS115
Kasper 2007LPS111
 MFH06
 LPS054
 SYN10
 SYN114
 SYN119
 LMS126
 LMS14
 SYN14
 SYN116
 LMS02
Kasper 2010SYN122
 MFH127
 LMS033
 MFH112
Kozuka 2002MFH132
 MHP023
Kurre 2000DSRCT026
 DSRCT042
Kushner 2008DSRCT048
Kushner 2001DSRCT08
Kushner 1996DSRCT023
 DSRCT121
 DSRCT013
 DSRCT034
Lafay-Cousin 2000DSRCT18
 DSRCT131
Lashkari 2009MFH099
Lippe 2003DSRCT134
Livaditi 2006DSRCT115
 DSRCT111
Madigan 2007RHA0104
Mazuryk 1998DSRCT019
Mingo 2005DSRCT136
Mitchell 1994ANG06
Navid 2006DSRCT13
 DSRCT115
Patel 2004MFH0 
 MFH1 
 MFH1 
 MFH1 
 MFH1 
 MFH1 
Recchia 2006MFH148
Saab 2007DSRCT116
 DSRCT12
 DSRCT14
 DSRCT017
Sung 2003MFH019
 CCS045
Watanabe 2006RHA036
Yamamura 2002MFH160
Yonemoto 1999SYN16
 SYN16
 SYN08
Total: 42 studiesPatients: 108

Alive: 49

Dead: 59

FU reported: 71
Treatment-related mortality

Treatment-related mortality (TRM) was addressed in 12 studies (163 transplanted participants). Ten of 12 studies reported a procedure-related death for 15 participants and two of 12 studies reported zero treatment-related deaths (Table 8). A conservative estimate of TRM was 5.5% (15 procedure-related deaths of a total of 275 transplanted patients).

Table 8. Treatment-related mortality (TRM)
  1. Blay 2000: The authors did not specify, whether the patient was among the 24 patients with adult-type sarcomas or among the 6 patients with rhabdomyosarcoma and Ewing's sarcoma both of which are not included in the present review.

    Cook 2012: 1 death within 100 days

StudyEvents (N)Cause of death
Aggregate comparative data (HDCT & autologous HSCT vs. SDCT)
Bui-Nguyen 20121Treatment-related leukemia death 2 years after HDCT
Aggregate case series data (HDCT & autologous HSCT only)
Bertuzzi 20030 
Bisogno 20100 
Blay 20001Sudden toxic death of unknown cause at day 29
Cook 20122Not specified
Philippe-Chomettte 20121Died of treatment toxicity 12 months after HDCT
Individual cases data (HDCT & autologous HSCT only)
Doros 20081Not specified
Engelhardt 20073Sepsis, sepsis, pulmonary metastases
Kasper 20071Cardiac arrest of unknown origin
Navid 20061Hepatic and renal failure
Saab 20072Acute myocardial infarction, veno-occlusive disease
Slease 19882Staphylococcus sepsis, progressive encephalopathy
Sum in 12 studies15 

Secondary outcomes

Disease-free survival

Cook 2012 reported an OS at three years of 23% regarding all patients and 40% versus 9% regarding patients with and without a complete response before HDCT respectively (Table 9).

Table 9. Disease-free survival (DFS)
  1. Cook 2012: all patients N = 36, patients that achieved complete remission before HDCT N = 13, patients that did not achieve complete remission before HDCT N =18

    Abbreviation: CI: confidence interval; HDCT: high-dose chemotherapy; HSCT: hematopoietic stem cell transplantation; DFS: disease-free survival

StudyDisease-free survival, % (95% CI)
Total assessedComplete response before the time of HSCTNot complete response before the time of HSCTT
Aggregate case series data (HDCT & autologous HSCT only)
Cook 20123 years: 23% (10 to 39)3 years: 40% (15 to 69)3 years: 9% (0 to 29)
Progression-free survival

Progression-free survival (PFS) was not statistically significantly different between HDCT and autologous HSCT versus SDCT in the RCT by Bui-Nguyen 2012 at three years (9.3% versus 21.6% with a HR of 1.34 (95% CI 0.81 to 2.20, P = 0.25)) (Table 10). The authors separately analyzed patients that had achieved a complete response to induction therapy before HDCT. PFS was higher in the complete response patients compared to all patients and OS was statistically significantly different between the treatment arms: OS among the patients that have achieved complete response at three years before HDCT was 20.0% versus 62.3% with a HR of 2.87 (95% CI 1.3 to 6.3, P = 0.009) (Table 10). Blay 2000 reported a considerable difference between the PFS of patients with complete response before HDCT at two and five years (62% versus 5%).

Table 10. Progression-free survival (PFS)
  1. Some estimates were deduced from Kaplan-Meier plot. Disease-free survival (DFS), event-free survival (EFS), failure-free survival (FFS), or health-related quality of life (HRQL) not reported.

    Bisogno 2010: Definition of endpoint: "For event-free survival (EFS), the interval between diagnosis and the date of latest follow-up, relapse or death was considered." In figure 1 of the article, the endpoint was designated as progression-free survival, which also is meaningful regarding the definition.

    (*) Blay 2000: including 5 patients with rhabdomyosarcoma and 1 patient with primitive neuroectodermal tumor

    Abbreviation: CI: confidence interval; HDCT: high-dose chemotherapy; HR: hazard ratio; HSCT: hematopoietic stem cell transplantation; PFS: progression-free survival; SDCT: standard-dose chemotherapy

StudyProgression-free survival (95% CI)
Total assessedComplete response before the time of HSCTNot complete response before the time of HSCT
Aggregate comparative data (HDCT & autologous HSCT vs. SDCT)
Bui-Nguyen 20123 years: 9.3% vs. 21.6%, HR 1.34 (0.81 to 2.20, P = 0.25)3 years: 20.0% vs. 62.3%, HR 2.87, (1.3 to 6.3, P = 0.009)Not reported
Aggregate case series data (HDCT & autologous HSCT only)
Bertuzzi 20032 years: 0%Not reportedNot reported
Bisogno 2010

2 years: 23%

3 years: 15.5%

Not reportedNot reported
Blay 2000Not reported

2 years: 62%

5 years: 62%

2 years: 5%

5 years: 5%

Bokemeyer 1997Median 8 months (range 2 to 19)Not reportedNot reported
Non-hematological toxicity grade 3 to 4

Non-hematological toxicity grade 3 to 4 was addressed in nine studies and a serious adverse event was described for 38 participants in nine studies (Table 11). A conservative estimate was 13.8% (38 events of non-hematological toxicity grade 3 to 4 in a total of 275 transplanted patients).

Table 11. Non-hematological toxicity grade 3 to 4
  1. Single-arm studies, only transplanted patients. Mucositis not included.

    Toxicity defined by National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), NCI 2009b.

StudyNon-hematological toxicity (N)Notice
NauseaMucositisKidneyLiverNervHeartOther
Aggregate comparative data (HDCT & autologous HSCT only)
Bui-Nguyen 201234    3Other: 2 infection, 1 pain
Aggregate case series data (HDCT & autologous HSCT only)  
Bisogno 2010 1     No grade IV organ dysfunctions
Blay 20008 5 10  
Bokemeyer 1997 22 1 1Nerv: central neurotoxicity; Other: septic episode
Individual cases data (HDCT & autologous HSCT only)  
Garrido 1998    1  Neuroleptic malignant syndrome
Kozuka 20021       
Kushner 2001    1   
Patel 2004  11  1Other: respiratory distress
Yonemoto 1999   1    
Sum1278240538 events in 105 patients of 9 studies
Secondary neoplasia

Secondary neoplasia was addressed in one case report (Table 12).

Table 12. Secondary neoplasia
  1. Single-arm studies, only transplanted patients.

StudyEventsDiagnosis
Individual cases data (HDCT & autologous HSCT only)
Yamamura 20031Chronic myelogenous leukemia
Health-related quality of life

Health-related quality of life scales were not addressed in the included studies.

Discussion

Summary of main results

Unlikein the first Cochrane systematic review published in 2011, we identified a randomized controlled trial (RCT) comparing HDCT followed by autologous HSCT to standard chemotherapy (SDCT) (Bui-Nguyen 2012). The authors reported a difference in overall survival (OS) after the treatment in favor of SDCT (32.7% versus 49.4%) but the difference was not statistically significant (HR 1.26, 95% CI 0.70 to 2.29, P = 0.44). Progression-free survival was also in favor of SDCT (9.3% versus 21.6%) but again the difference was not significant (HR 1.34, 95% CI 0.81 to 2.20, P = 0.25). Therefore, there is evidence that patients may not have a better survival after HDCT followed by autologous HSCT. If at all, this intervention should only be offered after careful consideration and only within controlled clinical trials. Of the participants, 20% have diagnoses not relevant to the present review and the 80% of participants with relevant diagnoses have 12 different types of NRSTS. The heterogeneity of types of NRSTS may be important because the OS may differ between the tumor types and the results of frequent types may overlay those of infrequent types.

We identified six case series reporting aggregate data that represented at least 80% of patients with NRSTS. These results described observed survival after a single experimental treatment. The results do not allow conclusions about an effect or benefit of this treatment that is not established. Of the six studies, four case series reported on transplanted patients with desmoplastic small round-cell tumors. OS at two years ranged between 20% and 51.4%. Two case series had a variety of NRSTS. Unfortunately they did not report Kaplan-Meier survival estimates. Our estimated OS of 50.6% at two years for the remaining studies with participant level data falls slightly below the upper limit of the range of 20% to 51.4% reported for six studies with aggregate data. Follow-up information was available for 65% (80 out of 123) of participants that could be included in the survival analysis.

For treatment-related mortality (TRM), even the more conservative estimate of 5.5% (15 out of 275 transplanted patients) is considerably higher than the 2.0% TRM within the first days following HSCT reported by the European Group for Blood and Marrow Transplantation (EBMT) Registry (EBMT 2009) for the year 1998 (Rosti 2002). Secondary neoplasia was reported for just one participant, which was probably an extreme underestimation of the true frequency because of the relatively short follow-up in the included studies and the fact that the included studies were not designed to specifically detect secondary neoplasia. The detection of secondary neoplasia depends on a long follow-up, which might be provided by cancer registers. This reported incidence compares with a frequency of 4.0% for secondary neoplasia based on register data (Neglia 2001) and 6.9% (Baker 2003) after a long observation period of 20 years. Non-hematological severe organ toxicity grade 3 to 4 was reported for 36% (38 of 105) transplanted patients with relevant NRSTS in nine studies. Lower grade and hematological toxicity were not included and should be accounted for to get a full picture of adverse events.

Overall completeness and applicability of evidence

Many of the studies we identified had to be excluded because they included participants with different heterogenous tumors without separate reporting, or the proportion of participants with NRSTS was fewer than 80%. Furthermore, some treatments were performed 10 to 20 years ago. Thus, the results may not be applicable to patients who are treated today. It is also a possibility that the results reflect the course of the disease and a consequence of the prior therapy rather than a consequence of the test intervention.

Quality of the evidence

The one RCT has a low risk of bias, whereas the remaining 48 studies were judged as having a high risk of bias. The characteristics of these single-arm studies showed that there are many different tumor types of NRSTS treated by transplantation, though each individual NRSTS entity was scarce. We found that a pooled survival analysis of individual participant data was considerably hampered. Specifically, the required follow-up information was incomplete or missing for 34% (37 out of 108) of participants and, therefore, corresponding data could not be included in the survival analysis. Each tumor type may carry an individual risk profile and, therefore, ideally should be evaluated separately. The body of evidence does not allow robust conclusions to be made in relation to the objectives of the review.

Potential biases in the review process

Strengths

The search strategy was broad and it is very likely that all relevant studies were identified. The WHO classification of NRSTS was adopted and modified to define a clear terminology for the study selection process. Studies were excluded if the proportion of non-eligible participants were greater or equal to 20% of the total population. Authors were contacted to ask for additional data.

Limitations

The results of studies may be difficult to compare because follow-up started at different time points, that is at diagnosis or at start of treatment. The delay between diagnosis and starting high-dose chemotherapy can be considerable. The median delay between diagnosis and intensification was four to 39 months in a study on 22 participants with STS including 11 NRSTS and 11 rhabdomyosarcoma patients (Dumontet 1992). We did a sensitivity analysis restricting the pooled analysis to individual cases that were followed from the start of the treatment and we excluded cases that were followed from diagnosis. However, we found only a very marginal difference in survival estimates.

We identified one RCT with a low risk of bias. This means that the results of this RCT may be used as evidence for the evaluation of the efficacy of autologous HSCT following HDCT for NRSTS. All other identified studies were single-arm studies with an inherent very high risk of bias. This means that the results of the single-arm studies are not helpful to decide whether autologous HSCT following HDCT for NRSTS is a meaningful treatment option. Many studies were excluded because participants with NRSTS were mixed with participants with other malignant diseases. The heterogeneity of NRSTS and the possible different terminology used in publications may have led us to overlook studies with eligible participants. This may be more an issue for case series but it is highly unlikely for controlled trials. The pooled survival analysis of individual data was based on less than half of all the individual data available and the exclusion of these data, whilst intending to reduce bias, may also have introduced bias.

Agreements and disagreements with other studies or reviews

We agree with Pedrazzoli 2006 that the potential benefit of this treatment option has not been investigated sufficiently in comparative studies. A systematic review (Verma 2008a) was performed to determine whether first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem cell transplantation improves outcomes compared with standard-dose chemotherapy in patients with inoperable, locally advanced or metastatic soft tissue sarcoma. Verma 2008a included only one case series (Schlemmer 2006) with HDCT followed by autologous HSCT, which was excluded from the present review because 40% of patients were not diagnosed with the disease of interest. Kasper 2005 concluded that the use of HDCT for locally advanced or metastatic adult (soft tissue and bone) sarcomas still remains highly investigational and should not be performed outside clinical trials.

Authors' conclusions

Implications for practice

The evidence base does not support the use of HDCT followed by autologous HSCT in high-risk patients with NRSTS. If this treatment is offered it should only be after careful consideration and integrated within a prospective concurrent, preferably randomized, controlled trial.

Implications for research

It is doubtful whether further studies are necessary to clarify the relevance of HDCT followed by autologous HSCT in patients with NRSTS. If non-randomized controlled studies are conducted, a low risk of bias should be achieved. Single-arm studies are not helpful. Criteria for the included tumor types should adhere to the WHO classification.

Acknowledgements

We thank the Cochrane Gynaecological Cancer Review Group for their assistance during the preparation of the review. The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, National Health Service (NHS) or the Department of Health. We thank Mandy Kromp, Nicolaus Kröger, and Michael Kulig for participating in the first version of the review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. New MEDLINE/Ovid search strategy

  1. soft tissue sarcoma?.mp.

  2. ((advanced or malignant) adj3 solid tumo?r?).mp.

  3. exp SARCOMA, ALVEOLAR SOFT PART/

  4. (alveolar soft part sarcoma? or alveolar soft tissue sarcoma?).mp.

  5. exp HEMANGIOSARCOMA/

  6. (angiosarcoma? or h?emangiosarcoma? or h?emangiopericytoma? or lymphangiosarcoma?).mp.

  7. exp SARCOMA, CLEAR CELL/

  8. (clear cell adj3 (sarcoma? or tumo?r?)).mp.

  9. exp DESMOPLASTIC SMALL ROUND CELL TUMOR/

  10. desmoplastic small round cell tumo?r?.mp.

  11. epithel?oid sarcoma?.mp.

  12. exp FIBROSARCOMA/

  13. (fibrosarcoma? or myxofibrosarcoma?).mp.

  14. fibromyxoid sarcoma?.mp.

  15. exp HEMANGIOENDOTHELIOMA/

  16. h?emangioendothelioma?.mp.

  17. exp HEMANGIOSARCOMA/

  18. h?emangioendotheliosarcoma?.mp.

  19. intimal sarcoma?.mp.

  20. exp LEIOMYOSARCOMA/

  21. leiomyosarcoma?.mp.

  22. exp LIPOSARCOMA/

  23. liposarcoma?.mp.

  24. exp HISTIOCYTOMA, MALIGNANT FIBROUS/

  25. (malignant fibrous histiocytoma? or spindle cell sarcoma?).mp.

  26. malignant glomus tumor.mp.

  27. exp HEMANGIOPERICYTOMA/

  28. malignant h?emangiopericytoma?.mp.

  29. MESENCHYMOMA.sh.

  30. malignant mesenchymoma?.mp.

  31. PERIVASCULAR EPITHELIOID CELL NEOPLASMS.sh.

  32. perivascular epithelioid cell tumor.mp.

  33. exp RHABDOID TUMOR/

  34. (rhabdoid tumo?r? or rhabdoid sarcoma?).mp.

  35. exp SARCOMA, SYNOVIAL/

  36. synovial sarcoma?.mp.

  37. exp HEMATOPOIETIC STEM CELL TRANSPLANTATION/

  38. TRANSPLANTATION, AUTOLOGOUS.sh.

  39. and/37-38

  40. (autologous adj6 transplant$).mp.

  41. bone marrow rescue.mp.

  42. bone marrow support.mp.

  43. bone marrow cell.mp.

  44. stem cell rescue.mp.

  45. stem cell support.mp.

  46. peripheral blood stem cell.mp.

  47. high dose chemotherapy.mp.

  48. myeloablative chemotherapy.mp.

  49. intensive chemotherapy.mp.

  50. dose intensive treatment.mp.

  51. high dose combination.mp.

  52. (ANIMALS not (ANIMALS and HUMANS)).sh.

  53. or/1-36

  54. or/39-51

  55. and/53-54

  56. 55 not 52

Appendix 2. New EMBASE/Ovid search strategy

  1. soft tissue sarcoma?.mp.

  2. ((advanced or malignant) adj3 solid tumo?r?).mp.

  3. exp ALVEOLAR SOFT PART SARCOMA/

  4. (alveolar soft part sarcoma? or alveolar soft tissue sarcoma?).mp.

  5. exp ANGIOSARCOMA/

  6. (angiosarcoma? or h?emangiosarcoma? or h?emangiopericytoma? or lymphangiosarcoma?).mp.

  7. exp CLEAR CELL SARCOMA/

  8. (clear cell adj3 (sarcoma? or tumo?r?)).mp.

  9. exp DESMOPLASTIC SMALL ROUND CELL TUMOR/

  10. desmoplastic small round cell tumo?r?.mp.

  11. exp EPITHELIOID SARCOMA/

  12. (epithelioid sarcoma? or epitheloid sarcoma?).mp.

  13. exp FIBROSARCOMA/

  14. (fibrosarcoma? or myxofibrosarcoma?).mp.

  15. fibromyxoid sarcoma?.mp.

  16. exp HEMANGIOENDOTHELIOMA/

  17. h?emangioendothelioma?.mp.

  18. exp HEMANGIOENDOTHELIOSARCOMA/

  19. h?emangioendotheliosarcoma?.mp.

  20. intimal sarcoma?.mp.

  21. exp LEIOMYOSARCOMA/

  22. leiomyosarcoma?.mp.

  23. exp LIPOSARCOMA/

  24. liposarcoma?.mp.

  25. exp MALIGNANT FIBROUS HISTIOCYTOMA/

  26. (malignant fibrous histiocytoma? or spindle cell sarcoma?).mp.

  27. malignant glomus tumor.mp.

  28. exp HEMANGIOPERICYTOMA/

  29. malignant h?emangiopericytoma?.mp.

  30. MESENCHYMOMA.sh.

  31. malignant mesenchymoma?.mp.

  32. mesenchymal sarcoma?.mp.

  33. PERIVASCULAR EPITHELIOID CELL TUMOR.sh.

  34. perivascular epithelioid cell tumor.mp.

  35. RHABDOID TUMOR.sh.

  36. (rhabdoid tumo?r? or rhabdoid sarcoma?).mp.

  37. exp SYNOVIAL SARCOMA/

  38. synovial sarcoma?.mp.

  39. exp AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION/

  40. (autologous adj6 transplant$).mp.

  41. bone marrow rescue.mp.

  42. bone marrow support.mp.

  43. bone marrow cell.mp.

  44. stem cell rescue.mp.

  45. stem cell support.mp.

  46. peripheral blood stem cell.mp.

  47. high dose chemotherapy.mp.

  48. myeloablative chemotherapy.mp.

  49. intensive chemotherapy.mp.

  50. dose intensive treatment.mp.

  51. (ANIMAL not (ANIMAL and HUMAN)).sh.

  52. or/1-38

  53. or/39-50

  54. and/52-53

  55. 54 not 51

Appendix 3. New Cochrane/Wiley search strategy

  1. soft tissue sarcoma?

  2. (advanced or malignant) adj3 solid tumo?r?

  3. MeSH descriptor: [Sarcoma, Alveolar Soft Part] explode all trees

  4. (alveolar soft part sarcoma?) or (alveolar soft tissue sarcoma?)

  5. MeSH descriptor: [Hemangiosarcoma] explode all trees

  6. angiosarcoma? or h?emangiosarcoma? or h?emangiopericytoma? or lymphangiosarcoma?

  7. MeSH descriptor: [Sarcoma, Clear Cell] explode all trees

  8. (clear cell adj3 (sarcoma? or tumo?r?))

  9. MeSH descriptor: [Desmoplastic Small Round Cell Tumor] explode all trees

  10. desmoplastic small round cell tumo?r?

  11. epithel?oid sarcoma?

  12. MeSH descriptor: [Fibrosarcoma] explode all trees

  13. (fibrosarcoma? or myxofibrosarcoma?)

  14. fibromyxoid sarcoma?

  15. MeSH descriptor: [Hemangioendothelioma] explode all trees

  16. h?emangioendothelioma?

  17. MeSH descriptor: [Hemangiosarcoma] explode all trees

  18. h?emangioendotheliosarcoma?

  19. intimal sarcoma?

  20. MeSH descriptor: [Leiomyosarcoma] explode all trees

  21. leiomyosarcoma?

  22. MeSH descriptor: [Histiocytoma, Malignant Fibrous] explode all trees

  23. (malignant fibrous histiocytoma? or spindle cell sarcoma?)

  24. malignant glomus tumor

  25. MeSH descriptor: [Hemangiopericytoma] explode all trees

  26. malignant h?emangiopericytoma?

  27. MeSH descriptor: [Mesenchymoma] explode all trees

  28. malignant mesenchymoma?

  29. MeSH descriptor: [Perivascular Epithelioid Cell Neoplasms] explode all trees

  30. perivascular epithelioid cell tumor

  31. MeSH descriptor: [Rhabdoid Tumor] explode all trees

  32. (rhabdoid tumo?r? or rhabdoid sarcoma?)

  33. MeSH descriptor: [Sarcoma, Synovial] explode all trees

  34. synovial sarcoma?

  35. MeSH descriptor: [Hematopoietic Stem Cell Transplantation] explode all trees

  36. MeSH descriptor: [Transplantation, Autologous] explode all trees

  37. (autologous adj6 transplant*)

  38. bone marrow rescue

  39. bone marrow support

  40. bone marrow cell

  41. stem cell rescue

  42. stem cell support

  43. peripheral blood stem cell

  44. high dose chemotherapy

  45. myeloablative chemotherapy

  46. intensive chemotherapy

  47. dose intensive treatment

  48. high dose combination

  49. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34

  50. #35 and #36

  51. #50 or #37 or #38 or #39 or #40 or #41 #42 or #43 or #44 or #45 or #46 or #47 or #48

  52. #49 and #51

Appendix 4. Original MEDLINE/Ovid search strategy

  1. exp SARCOMA/

  2. (sarcom$ or sarkom$).mp.

  3. exp LIPOSARCOMA/

  4. liposar#om$.mp.

  5. exp FIBROSARCOMA/

  6. fibrosar#om$.mp.

  7. exp HISTIOCYTOMA, MALIGNANT FIBROUS/

  8. malign$ fibrous histio#ytom$.mp.

  9. exp LEIOMYOSARCOMA/

  10. leiomyosar#om$.mp.

  11. malign$ glom$ tumo$.mp.

  12. exp RHABDOMYOSARCOMA/

  13. rhabdomyosar#om$.mp.

  14. exp HEMANGIOENDOTHELIOMA/

  15. (hemangioendotheliom$ or haemangioendotheliom$).mp.

  16. exp HEMANGIOSARCOMA/

  17. (angiosar#om$ or hemangiosar#om$ or haemangiosar#om$).mp.

  18. exp SARCOMA, SYNOVIAL/

  19. synovia$ sar#om$.mp.

  20. epithelioid sar#om$.mp.

  21. exp SARCOMA, ALVEOLAR SOFT PART/

  22. (alveolar soft part sar#om$ or alveolar soft tissue sar#om$).mp.

  23. exp SARCOMA, CLEAR CELL/

  24. clear cell sar#om$.mp.

  25. exp SARCOMA, SMALL CELL/

  26. (desmoplastic and small round cell tumo$ or small cell tumo$)).mp.

  27. exp RHABDOID TUMOR/

  28. ((extrarenal or extra-renal) and rhabdoid tumo$).mp.

  29. (malignan$ and mesenchymom$).mp.

  30. clear cell myomelano#ytic tumo$.mp.

  31. intima$ sar#om$.mp.

  32. exp STEM CELL TRANSPLANTATION/

  33. exp BONE MARROW TRANSPLANTATION/

  34. exp TRANSPLANTATION, AUTOLOGOUS/

  35. exp TRANSPLANTATION, HOMOLOGOUS/

  36. exp TRANSPLANTATION, CONDITIONING/

  37. (autolog$ hemato$ or autolog haemato$ or autolog$ stem cell or autolog$ bone marrow or autolog$ periph$ or autolog$ transplant$ or autolog$ graft$ or autotransplant$ or auto-transplant$ or autograft$ or auto-graft$).mp.

  38. (homolog$ hemato$ or homolog$ haemato$ or homolog$ stem cell or homolog$ bone marrow or homolog$ cord or homolog$ umbilical or homolog$ peripheral or homolog$ transplant$ or homolog$ graft$ or homolog$ transplant$).mp.

  39. (stem cell transplant$ or bone marrow transplant$ or periph$ blood stem cell or periph$ stem cell or cord blood transplant$).mp.

  40. (reduced intens$ or myeloablat$ or nonmyeloablat$ or non-myeloablat$).mp.

  41. high dose chemotherapy.mp.

  42. or/1-31

  43. or/32-41

  44. and/42-43

  45. (ANIMALS not (ANIMALS and HUMANS)).sh.

  46. 44 not 45

Appendix 5. Original EMBASE/Ovid search strategy

  1. exp SARCOMA/

  2. (sarcom$ or sarkom$).mp.

  3. exp LIPOSARCOMA/

  4. liposar#om$.mp.

  5. exp FIBROSARCOMA/

  6. fibrosar#om$.mp.

  7. exp MALIGNANT FIBROUS HISTIOCYTOMA/

  8. malign$ fibrous histio#ytom$.mp.

  9. exp LEIOMYOSARCOMA/

  10. leiomyosar#om$.mp.

  11. malign$ glom$ tumo$.mp.

  12. exp RHABDOMYOSARCOMA/

  13. rhabdomyosar#om$.mp.

  14. exp HEMANGIOENDOTHELIOMA/

  15. (hemangioendotheliom$ or haemangioendotheliom$).mp.

  16. exp HEMANGIOENDOTHELIOSARCOMA/

  17. (hemangioendotheliosar#om$ or haemangioendotheliosar#om$).mp.

  18. exp ANGIOSARCOMA/

  19. angiosar#om$.mp.

  20. exp SYNOVIAL SARCOMA/

  21. synovia$ sar#om$.mp.

  22. exp EPITHELIOID SARCOMA/

  23. (epithelioid$ sar#om$ or epitheloid$ sar#om$).mp.

  24. exp ALVEOLAR SOFT PART SARCOMA/

  25. (alveolar soft part sar#om$ or alveolar soft tissue sar#om$).mp.

  26. exp CLEAR CELL SARCOMA/

  27. clear cell sar#om$.mp.

  28. exp DESMOPLASTIC SMALL ROUND CELL TUMOR/

  29. exp SMALL CELL SARCOMA/

  30. (desmoplastic and (small round cell tumo$ or small cell tumo$)).mp.

  31. ((extrarenal$ or extra-renal$) and rhabdoid$ tumo$).mp.

  32. (malign$ and mesenchymom$).mp.

  33. clear cell myomelano#yt$ tumo$.mp.

  34. intima$ sar#om$.mp.

  35. exp STEM CELL TRANSPLANTATION/

  36. exp BONE MARROW TRANSPLANTATION/

  37. exp NONMYELOABLATIVE STEM CELL TRANSPLANTATION/

  38. exp NONMYELOBLATIVE CONDITIONING/

  39. exp REDUCED INTENSITY CONDITIONING/

  40. exp MYELOABLATIVE CONDITIONING/

  41. (autolog$ hemato$ or autolog haemato$ or autolog$ stem cell or autolog$ bone marrow or autolog$ periph$ or autolog$ transplant$ or autolog$ graft$ autotransplant$ or auto-transplant$ or autograft$ or auto-graft$).mp.

  42. (homolog$ hemato$ or homolog$ haemato$ or homolog$ stem cell or homolog$ bone marrow or homolog$ cord or homolog$ umbilical or homolog$ periph$ or homolog$ transplant$ or homolog$ graft$).mp.

  43. (stem cell transplant$ or bone marrow transplant$ or periph$ blood stem cell or periph$ stem cell or cord blood transplant$).mp.

  44. (reduced intens$ or myeloablat$ or nonmyeloablat$ or non-myeloablat$).mp.

  45. high dose chemotherapy.mp.

  46. or/1-34

  47. or/35-45

  48. and/46-47

  49. (ANIMALS not (ANIMALS and HUMANS)).sh.

  50. 48 not 49

Appendix 6. Original Cochrane/Wiley search strategy

  1. exp SARCOMA/

  2. (sarcom$ or sarkom$).mp.

  3. exp LIPOSARCOMA/

  4. liposar#om$.mp.

  5. exp FIBROSARCOMA/

  6. fibrosar#om$.mp.

  7. exp HISTIOCYTOMA, MALIGNANT FIBROUS/

  8. malign$ fibrous histio#ytom$.mp.

  9. exp LEIOMYOSARCOMA/

  10. leiomyosar#om$.mp.

  11. malign$ glom$ tumo$.mp.

  12. exp RHABDOMYOSARCOMA/

  13. rhabdomyosar#om$.mp.

  14. exp HEMANGIOENDOTHELIOMA/

  15. (hemangioendotheliom$ or haemangioendotheliom$).mp.

  16. exp HEMANGIOSARCOMA/

  17. (angiosar#om$ or hemangiosar#om$ or haemangiosar#om$).mp.

  18. exp SARCOMA, SYNOVIAL/

  19. synovia$ sar#om$.mp.

  20. (epithelioid sar#om$ or epitheloid sar#om$).mp.

  21. exp SARCOMA, ALVEOLAR SOFT PART/

  22. (alveolar soft part sar#om$ or alveolar soft tissue sar#om$).mp.

  23. exp SARCOMA, CLEAR CELL/

  24. clear cell sar#om$.mp.

  25. exp SARCOMA, SMALL CELL/

  26. (desmoplastic and (small round cell tumo$ or small cell tumo$)).mp.

  27. exp RHABDOID TUMOR/

  28. ((extrarenal or extra-renal) and rhabdoid tumo$).mp.

  29. (malignan$ and mesenchymom$).mp.

  30. clear cell myomelano#ytic tumo$.mp.

  31. intima$ sar#om$.mp.

  32. exp STEM CELL TRANSPLANTATION/

  33. exp BONE MARROW TRANSPLANTATION/

  34. exp TRANSPLANTATION, AUTOLOGOUS/

  35. exp TRANSPLANTATION, HOMOLOGOUS/

  36. exp TRANSPLANTATION, CONDITIONING/

  37. (autolog$ hemato$ or autolog haemato$ or autolog$ stem cell or autolog$ bone marrow or autolog$ periph$ or autolog$ transplant$ or autolog$ graft$ or autotransplant$ or auto-transplant$ or autograft$ or auto-graft$).mp.

  38. (homolog$ hemato$ or homolog$ haemato$ or homolog$ stem cell or homolog$ bone marrow or homolog$ cord or homolog$ umbilical or homolog$ periph$ or homolog$ transplant$ or homolog$ graft$).mp.

  39. (stem cell transplant$ or bone marrow transplant$ or periph$ blood stem cell or periph$ stem cell or cord blood transplant$).mp.

  40. (reduced intens$ or myeloablat$ or nonmyeloablat$ or non-myeloablat$).mp.

  41. high dose chemotherapy.mp.

  42. or/1-31

  43. or/32-41

  44. and/42-43

  45. (ANIMALS not (ANIMALS and HUMANS)).sh.

  46. 44 not 45

What's new

DateEventDescription
21 September 2016AmendedContact details updated.

History

Protocol first published: Issue 1, 2010
Review first published: Issue 2, 2011

DateEventDescription
1 April 2015AmendedContact details updated.
24 February 2015AmendedContact details updated.
11 February 2015AmendedContact details updated.
27 March 2014AmendedContact details updated.
10 June 2013New citation required and conclusions have changedWe identified a single randomized controlled trial and judged it to have a low risk of bias. The results did not support high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation compared to standard-dose chemotherapy in patients with non-rhabdomyosarcoma soft tissue sarcoma.
5 December 2012New search has been performedSearches re-run and one new study included.

Contributions of authors

FP: designing and coordinating the review, data collection for the review, designing search strategies, undertaking searches, screening search results, organizing retrieval of papers, screening retrieved papers against eligibility criteria, appraising quality of papers, extracting data from papers, writing to authors of papers for additional information, data management for the review, entering data into RevMan, analysis of data, interpretation of data, writing the update

LAS: providing methodological advice, appraising quality of papers

CB: screening retrieved papers against eligibility criteria, extracting data from papers, screening included papers to verify data, interpretation of data

Declarations of interest

The authors declare that they have no competing interests.

Sources of support

Internal sources

  • University of Cologne, Germany.

    Provision of fulltexts

External sources

  • No sources of support supplied

Differences between protocol and review

Differences between the recent version and the updated version of the review

It is not clear that the unclassified and the undifferentiated tumor types are non-rhabdomyosarcoma soft tissue sarcomas. Therefore, we did not consider these tumor types for the present review and relocated both types from the list of included to the list of excluded tumor types. As a result, the following seven studies were included in the original review but excluded in the update: Endo 1996; Frapier 1998; Mesia 1994; Nakamura 2008; Ronghe 2004; Shaw 1996; Watanabe 2006.

In contrast to the recent version, we excluded the article by Ivanova 2007. According to e-mail correspondence with the author AB Shvarova of a related article (Ivanova 2010) and co-worker at the same research institution, the proportion of patients with NRSTS was less than 50%. Most of the retrospectively observed patients were children diagnosed with rhabdomyosarcoma. In contrast to the recent version, we included the study by Blay 2000 because we accepted the results of a subgroup analysis comprising 91% (22 out of 24) relevant patients. In agreement with the recent version, the exclusion of the study by Schlemmer 2006 based on a proportion of NRSTS patients below 80% was confirmed according to a recent author contact.

We complemented PFS estimates. We conducted an updated search and included five further studies (Bisogno 2010; Buerk 2010; Hara 2010; Houet 2010; Jordan 2010) that were identified in the update and therefore not reported in the recent version. One study reported aggregate data of 14 participants (Bisogno 2010) and three studies reported individual data of nine participants which were suitable for inclusion in the meta-analysis (Buerk 2010; Hara 2010; Jordan 2010).

Concerning the two articles by Kasper 2007a and Kasper 2010, we stated in the recent version that some participants were reported in both articles. In the present updated version, we evaluated these duplicate data and identified six participants by coincidental information on age, histology, and metastatic sites. We included eight instead of 14 participants reported by Kasper 2007a and seven participants reported by Kasper 2010. Consequently, we removed the duplicate data of six participants from the pooled analysis. We did not find additional reviews in the updated search.

We changed the search strategy to increase the fraction of the identified relevant documents of all identified relevant and not relevant documents (precision). The new search strategy is more economical in terms of spending resources for study selection for the present review and also for future updates. The new search strategy was not only used for the time period to be updated but was used from inception of all electronic databases searched. The screening process was redone regarding the complete retrieved records. All identified studies were evaluated in detail regardless of being part of the original review. We considered and re-evaluated all studies that were included in the original review. Therefore, the search strategy is composed of two parts. The new more narrow strategy is spanning the time from inception to 5 December 2012. The old more broad strategy is spanning from inception to 5 February 2010.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al Balushi 2009

Methods

Duration: 2000 to 2007

Study design: retrospective report of cases without control

Treatment: number of arms: 1

Follow-up time: 18, 24, and 72 months for 3 transplanted participants

Participants

Setting: single center in Canada

Eligibility criteria: patients with desmoplastic small round-cell tumor

Number of participants: 5 patients with desmoplastic small round-cell tumor

  • 3 transplanted patients with metastatic desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 2 patients without HSCT

Age: not specified

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): all 5 patients were treated with a total of 4 cycles of chemotherapy regimen that includes doxorubicin 270 to 375 mg/m2, ifosfamide 36000 to 58000 mg/m2, cyclophosphamide 12500 to 21000 mg/m2, and etoposide 2700 to 4350 mg/m2 total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • Stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Andres 2006

Methods

Duration: August to October 2002

Study design: retrospective report of a single cases without control

Treatment: number of arms: 1

Follow-up time: 10 months for 1 transplanted participant

Participants

Setting: single center in Spain

Eligibility criteria: 1 patient with desmoplastic small round-cell tumor, no metastases

Number of participants: 1 patient

  • 1 transplanted patient with desmoplastic small round-cell tumor (included in the present review)

Age: 21 years old

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): thiotepa 1200 mg/m2, carboplatin 2000 mg/m2, and cyclophosphamide 9600 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • Stem cell source: not specified ("stem cell rescue")

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bernbeck 2007

Methods

Duration: 2001 to 2005

Study design: retrospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not reported

Participants

Setting: single center in Germany

Eligibility criteria: high-risk soft tissue sarcomas, that means patients that are refractory to conventional therapy (incomplete response or relapse) or may have metastases

Number of participants: 9 patients

  • 2 transplanted patients with synovial sarcoma with metastases (included in the present review)

  • not included in the present review: 6 patients with rhabdomyosarcoma

  • not included in the present review: 1 patient with Ewing sarcoma

Age: 21 and 21 years old

Gender: 1 male, 1 female

Interventions

High-dose chemotherapy (HDCT): topotecan 3.75 mg/m2, etoposide 500 mg/m2, carboplatin 500 mg/m2, and cyclophosphamide 1000 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • Stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: the authors have no conflict of interest to disclose
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bertuzzi 2003

Methods

Duration: 1997 to 2002

Study design: prospective study of consecutive cases without control

Treatment: number of arms: 1

Follow-up time: time to event analysis with 2 year follow-up of transplanted participants, median follow-up 35 months

Participants

Setting: single center in Italy

Eligibility criteria: advanced desmoplastic small round-cell tumor at various clinical stages including 4 patients with metastases

Number of participants: 10 patients

  • 10 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

Age: median 29 years of age (range 15 to 60 years)

Gender: 10 males

Interventions

High-dose chemotherapy (HDCT): after a four-course induction phase, patients in complete or partial response received HDCT with melphalan 160 mg/m2 plus mitoxantrone 60 mg/m2 or thiotepa 600 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • Stem cells source: peripheral blood

Outcomes

Primary outcomes: overall survival and treatment-related mortality ("no toxic deaths were observed") reported as aggregate data

Secondary outcomes: progression-free survival reported as aggregate data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designLow riskProspective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bisogno 2010

Methods

Duration: 1999 to 2008

Study design: prospective study of cases without control

Treatment: number of arms: 1

Follow-up time: time to event analysis with 3 year follow-up of transplanted participants with a median follow-up of 27 months for survivors

Participants

Setting: multi-center study in Italy

Eligibility criteria: desmoplastic small round-cell tumor at various clinical stages including 4 patients with metastases

Number of participants: 14 patients

  • 14 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

Age: median 10.3 years of age (range 2 to 17.8 years)

Gender: 13 males, 1 female

Interventions

High-dose chemotherapy (HDCT): after an induction phase of nine weeks, three consecutive intensified-dose combinations were applied: thiotepa 300 mg/m2, melphalan 60 mg/m2, cyclophosphamide 4000 mg/m2, thiotepa 300 mg/m2, and melphalan 80 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as aggregate data

Secondary outcomes: progression-free survival reported as aggregate data; toxicity reported as individual data

Notes

Conflict of interest: "The authors have no conflict of interest to disclose."

Support: "This research was partially supported by a grant from the Fondazione Citta della Spiranza."

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designLow riskProspective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Blay 2000

Methods

Duration: 1988 to 1994

Study design: prospective study of cases without control

Treatment: number of arms: 1

Follow-up time: time to event analysis with 5 year follow-up of transplanted participants with a median follow-up of 94 months for survivors

Participants

Setting: single center in France

Eligibility criteria: advanced soft tissue sarcomas

Number of participants: 30 patients, 26 patients had distant metastases and the rest of 4 had a locally advanced stage

  • 24 transplanted patients analyzed in a subgroup of patients with adult-type sarcomas excluding rhabdomyosarcoma and Ewing family of tumors; this subgroup analysis compared patients who have achieved a complete response before HDCT with those who had a partial or minor response (included in the present review, 80% of all participants)

    • 22 transplanted patients with NRSTS: 5x leiomyosarcoma, 4x synovial sarcoma, 4x undifferentiated sarcoma, 3x unclassified sarcoma, 2x angiosarcoma, 2x liposarcoma, 1x fibrosarcoma, 1x hemangiopericytoma

    • not included in the present review: 1x paraganglioma, 1x Schwannosarcoma

  • not included in the present review: 5 patients with rhabdomyosarcoma

  • not included in the present review: 1 patient with extraskeletal permeative neuroectodermal tumor (PNET)

Age: median 34 years of age (range 17 to 57 years)

Gender: 17 males, 13 female

Interventions

High-dose chemotherapy (HDCT): the majority of patients had received induction chemotherapy, afterwards HDCT was applied that comprised etoposide 800 mg/m2, cisplatin 200 mg/m2, ifosfamide 12000 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow (N = 25) or peripheral blood (N = 5)

Outcomes

Primary outcomes: overall survival reported as aggregate data, treatment-related mortality "one sudden toxic death"

Secondary outcomes: progression-free survival and toxicity reported as aggregate data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designLow riskProspective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bley 2004

Methods

Duration: no information on observation period available

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 7 months for 1 transplanted participant

Participants

Setting: single center in Germany

Eligibility criteria: liposarcoma

Number of participants: 1 patient

  • 1 transplanted patient with liposarcoma and with autologous HSCT (included in the present review)

Age: 22 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): melphalan and busulfan

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Boelke 2005

Methods

Duration: in 1993

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 89 months for 1 transplanted participant

Participants

Setting: single center in Germany

Eligibility criteria: malignant fibrous histiocytoma

Number of participants: 1 patient

  • 1 transplanted patient with recurrent malignant fibrous histiocytoma and with autologous HSCT (included in the present review)

Age: 33 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): melphalan and busulfan

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bokemeyer 1997

Methods

Duration: no information on observation period available

Study design: retrospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: patients were presumably treated in 3 centers in Germany according to author affiliation

Eligibility criteria: histologically proven metastatic or advanced adult soft tissue sarcoma without prior treatment, age between 18 and 60 years, a Karnofsky index greater than or equal to 50%, adequate liver, kidney, and bone marrow function

Number of participants: 18 patients

  • 16 transplanted patients with NRSTS and with autologous HSCT: 5x malignant fibrous histiocytoma, 4x hemangiopericytoma, 3x synovial sarcoma, 2x leiomyosarcoma, 2x mesenchymal sarcoma (included in the present review)

  • not included in the present review: 2x malignant Schwannoma

Age: median 45 (range 25 to 57) years of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): doxorubicin, 75 mg/m2, ifosfamide at different dose levels 8000, 10000, 12000, 14000, or 16000 mg/m2, total dose

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as aggregate data

Secondary outcomes: progression-free survival, toxicity reported as aggregate data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Buerk 2010

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 6 weeks for 1 transplanted participant

Participants

Setting: single center in Germany

Eligibility criteria: angiosarcoma

Number of participants: 1 patient

  • 1 transplanted patient with epithelioid angiosarcoma of the scapula without distant metastases (included in the present review)

Age: 48 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Bui-Nguyen 2012

Methods

Duration: 2000 to 2008

Study design: randomized controlled trial: "This open, multicenter, randomized phase III study [...]". "All patients eligible for preenrollment received the same baseline treatment [...]". "[...] eligible for randomization if they had responded to chemotherapy or, for stable disease, if a complete surgical resection of all disease sites could be carried out. Patients were ineligible for randomization if they had progressed or had only stable disease with no possibility for complete resection of the primary and/or metastatic tumor". "Randomization was stratified by center using a blocked method with block size of four and was carried out centrally". "The intention to treat (ITT)-modified population included all randomly assigned patients excluding patients found to be ineligible at central histology review."

Treatment: number of arms: 2

Follow-up time: time to event analysis at 3 years with a median follow-up of 55 months for survivors

Participants

Setting: multicenter trial in 16 centers in France

Eligibility criteria: patients aged 18 to 65 years with histologically confirmed, inoperable locally advanced or metastatic soft tissues sarcomas; Eastern Cooperative Oncology Group performance status of 0 or 1; normal cardiac, hepatic, and renal function, adequate bone marrow reserve; patients had received no prior chemotherapy or concurrent therapy; patients for whom it was possible to perform potentially curative locoregional treatments and patients with uterine, bone, or digestive tumors were excluded.

Number of participants: 264

  • 264 patients pre-enrolled

  • 207 patients received first 4 of 6 chemotherapy courses

  • 87 patients were randomized to HDCT plus autologous HSCT (N = 41, but data from 38 analyzed in ITT) and to SDCT (N = 46, but data from 45 analyzed in ITT)

    • 69 patients with NRSTS: 16x leiomyosarcoma, 16x malignant fibrous histiocytoma, 10x others (2x undifferentiated sarcoma, 2x malignant myoepithelioma, 1x leiomyosarcoma, 1x fibrosarcoma, 1x myofibrosarcoma, 1x unclassified sarcoma, 1x desmoplastic small round cell sarcoma), 10x liposarcoma, 9x synovial sarcoma, 6x angiosarcoma, 1x clear cell sarcoma, 1x desmoplasatic round cell sarcoma (included in the present review)

    • not included in the present review: 18 patients (20%) with diagnoses other than NRSTS: 9x rhabdomyosarcoma, 2x malignant peripheral nerve sheath tumor, 1x osteosarcoma, 1x melanoma, 5x others (3x endometrial stromal sarcoma, 1x gastro-intestinal stromal tumor, 1x triton tumor)

  • 83 patients were included in modified intention to treat analysis (ITT) to compare overall survival and progression-free survival between treatment groups; histologically ineligible patients were excluded from primary group of analysis, 3 from the HDCT plus autologous HSCT group with data from 38 patients used for ITT analysis and 1 from the SDCT group with data from 45 patients used for ITT analysis

  • 62 patients received the assigned treatment and were included in the toxicity analysis

Age: range 18.5 to 65.0 years of age, median 45.8, in the HDCT arm and 18.7 to 65.0 years of age, median 43.3, in the SDCT arm

Gender: 58.5% (24 of 41) males in the HDCT arm and 50% (23 of 46) males in the CDCT arm

Interventions

All participants received 5 times standard-dose chemotherapy: doxorubicin 60 mg/m2, ifosfamide 7500 mg/m2, dacarbazine 900 mg/m2, total doses; the sixth course was different between arm 1 and 2:

Randomized to arm 1, sixth course:

  • High-dose chemotherapy (HDCT): ifosfamide 10000 mg/m2, carboplatin, and etoposide 1200 mg/m2, total doses

  • Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

  • actually 22 of 41 randomized patients received HDCT followed by HSCT

Randomized to arm 2, sixth course:

  • Standard-dose chemotherapy: doxorubicin 60 mg/m2, ifosfamide 7500 mg/m2, dacarbazine 900 mg/m2, total doses

  • actually 40 of 46 randomized patients received standard-dose chemotherapy

Outcomes

Primary outcomes:

  • Overall survival reported as aggregate data; individual data were not reported

Secondary outcomes:

  • Progression-free survival reported as aggregate data; individual data were not reported

  • Toxicity reported as individual data

Notes

Financial support: Programme Hospitalier de Recherche Clinique, French Health Ministry (non-profit organization); French National Federation for Comprehensive Cancer Centers (non-profit organization).

Information about the histological type of sarcoma designated as "others" in the article were communicated by personal contact with the first author.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization was stratified by center using a blocked method with block size of four and was carried out centrally"
Allocation concealment (selection bias)Unclear riskAllocation was carried out centrally, though, masking of allocation was not described in full detail.
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome. It was denoted as an "open, multicenter, randomized phase III study".
Selective reporting (reporting bias)Low riskWe did not detect reporting of outcomes that might be selective
Prospective designLow riskRandomized controlled trial
Comparable baseline characteristicsLow riskBaseline data including pretreatment were comparable. "All patients eligible for preenrollment received the same baseline treatment".
Assignment of patients to treatment groupsLow riskRandomized controlled trial
Concurrent controlLow riskRandomized controlled trial
Loss to follow-upLow riskLoss to follow-up was described and modified intention-to-treat analysis was performed

Cole 1999

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 6 months for 1 transplanted participant

Participants

Setting: single center in the United States

Eligibility criteria: synovial sarcoma

Number of participants: 1 patient

  • 1 transplanted patient with synovial sarcoma (included in the present review)

Age: 26 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Cook 2012

Methods

Duration: 1999 to 2007

Study design: retrospective registry analysis of cases without control reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Treatment: number of arms: 1

Follow-up time: median of 44 months (range 4 to 89) for survivors

Participants

Setting: analysis of registry data from 29 centers reported to CIBMTR located in North America except for 3 patients

Eligibility criteria: desmoplastic small round cell tumor

Number of participants: 36 patients

  • 36 transplanted patients (included in the present review)

Age: median 19 years of age (range 8 to 46 years)

Gender: 29 males, 7 females

Interventions

High-dose chemotherapy (HDCT): the most common agents were thiotepa, etoposide, melphalan, cyclophosphamide, and carboplatin

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow (N = 2) or peripheral blood (N = 33), information missing in 1 patient

Outcomes

Primary outcomes: overall survival and treatment-related mortality reported as aggregate data

Secondary outcomes: disease-free survival reported as aggregate data

Notes

Financial support of CIBMTR:

Grants from non-profit organizations:

  • Blue Cross and Blue Shield Association

  • Children’s Leukemia Research Association

  • National Cancer Institute (NCI)

  • National Heart, Lung and Blood Institute (NHLBI)

  • National Institute of Allergy and Infectious Diseases (NIAID)

  • Office of Naval Research

Grants from biopharmaceutical companies

  • Allos, Inc

  • Amgen, Inc.

  • Celgene Corporation

  • CellGenix, GmbH

  • Fresenius-Biotech North America, Inc.

  • Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.

  • Genzyme Corporation

  • GlaxoSmithKline

  • Kiadis Pharma

  • Millennium Pharmaceuticals, Inc.

  • Milliman USA, Inc.

  • Miltenyi Biotec, Inc.

  • Optum Healthcare Solutions, Inc.

  • Otsuka America Pharmaceutical, Inc.

  • Seattle Genetics

  • Sigma-Tau Pharmaceuticals

  • Soligenix, Inc.

  • Swedish Orphan Biovitrum AB

  • THERAKOS, Inc.

  • Wellpoint, Inc.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Doros 2008

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 0 months for 1 transplanted participant

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 1 patient

  • 1 transplanted patient with desmoplastic small round-cell tumor (included in the present review)

Age: 14 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified ("autologous stem cell rescue")

Outcomes

Primary outcomes: overall survival and treatment-reported mortality reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Engelhardt 2007

Methods

Duration: 1992 to 2003

Study design: retrospective report of a consecutive series of cases without controls

Treatment: number of arms: 1

Follow-up time: not specified for individual participants

Participants

Setting: an international multicenter study, the number of centers and the name of participating countries were not specified and presumably included Germany and the United States

Eligibility criteria: high-risk Ewing sarcoma and soft tissue sarcomas, 18 years or older, tumor diameter 5 cm or more, extensive local or distant recurrence and/or metastatic disease, histologically moderately differentiated or undifferentiated tumors

Number of participants: 35 patients

  • 23 transplanted patients with NRSTS including anaplastic soft tissue sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant hemangioperiocytoma, synovial sarcoma (included in the present review)

  • not included in the present review: 8 patients with Ewing sarcoma

  • not included in the present review: 3 patients with rhabdomyosarcoma

  • not included in the present review: 1 patient with Schwannoma

Age: range 21 to 56 years of age of 23 patients with NRSTS

Gender: 12 males and 11 females of 23 patients with NRSTS

Interventions

High-dose chemotherapy (HDCT): various regimens for individual patients

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival and treatment-related mortality reported as individual data
Notes

The reported aggregate data were not considered because the proportion of participants with NRSTS was 67% (23 of 35). A proportion of at least 80% is required for extracting aggregate data.

Financial support: not addressed

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Etienne-Mastroianni 2002

Methods

Duration: 1970 to 1999

Study design: retrospective report of cases without controls

Treatment: number of arms: 1

Follow-up time: 3 to 144 months (mean 42)

Participants

Setting: single center in France

Eligibility criteria: primary sarcoma of the lung, metastatic pulmonary sarcomas, as well as mediastinal, thoracic wall, pleural, and cardiac primary sarcomas were excluded; 15 years of age or older

Number of participants: 12 patients

  • 1 transplanted patient with leiomyosarcoma (included in the present review)

  • not included in the present review: 11 patients without transplantation

Age: 50 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: not reported individually

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Fang 2008

Methods

Duration: in 2006

Study design: retrospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: high-risk solid tumor of childhood

Number of participants: 2 patients

  • 1 transplanted patient with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 1 patient with desmoplastic small round-cell tumor but no autologous HSCT

Age: 23 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: not reported individually

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Farruggia 2008

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 36 months

Participants

Setting: single center in Italy

Eligibility criteria: synovial sarcoma

Number of participants: 1 patient

  • 1 transplanted patient with synovial sarcoma (included in the present review)

Age: 10 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): carboplatin 500 mg/m2, epirubicine 150 mg/m2, vincristine 1.5 mg/m2 / ifosfamide 3000 mg/m2, vincristine 1.5 mg/m2, etoposide 150 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Fetscher 1996

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 1 month

Participants

Setting: single center in Germany

Eligibility criteria: nuchal leiomyosarcoma

Number of participants: 1 patient

  • 1 transplanted patient with leiomyosarcoma (included in the present review)

Age: 53 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Fetscher 1997

Methods

Duration: in 1994

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 36 months

Participants

Setting: single center in Germany

Eligibility criteria: gastric leiomyosarcoma

Number of participants: 1 patient

  • 1 transplanted patient with metastatic leiomyosarcoma (included in the present review)

Age: 23 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): etoposide 1500 mg/m2, ifosfamide 12000 mg/m2, carboplatin 1500 mg/m2, epirubicine 150 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Fraser 2006

Methods

Duration: 1995 to 2004

Study design: prospective series of cases without control

Treatment: number of arms: 1

Follow-up time: not specified for individual data

Participants

Setting: single center in the United States

Eligibility criteria: patients with a range of high-risk solid and brain tumors who had achieved a complete or partial response with non-progessive disease; patients had high-risk tumors that were either metastatic at diagnosis or had relapsed following therapy; adequate organ function was documented

Number of participants: 36 patients

  • 4 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 32 patients with other solid tumors such as 16x Ewing's sarcoma, 3x rhabdomyosarcoma, 2x Wilm's tumor, 2x ovarian tumor, 2x medulloblastoma, 1x hepatoblastoma, 1x retinoblastoma, 1x osteosarcoma, 1x glioblastoma multiforme, 1x ependymoma, 1x chordoma, 1 patient with cerebral rhabdoid tumor

Age: 8, 10, 14, 20 years of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): busulfan 12 mg/kg, melphalan 100 mg/m2, thiotepa 500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow or peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: "This work was supported in part by a grant from the Children’s Cancer Research Fund." (national nonprofit organization)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Garrido 1998

Methods

Duration: 1991 to 1995

Study design: retrospective report of 2 cases without control

Treatment: number of arms: 1

Follow-up time: not specified for individual data

Participants

Setting: single center in the United States

Eligibility criteria: neuroleptic malignant syndrome after transplantation

Number of participants: 2 patients

  • 1 transplanted patient with metastatic liposarcoma (included in the present review)

  • not included in the present review: 1 transplanted patient with breast carcinoma

Age: 45 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): busulfan 12 mg/kg total dose, melphalan 100 mg/m2 total dose, thiotepa 500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: not reported

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Graham 1997

Methods

Duration: 1991 to 1995

Study design: prospective report of a cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: recurrent and high-risk pediatric brain tumors after transplantation

Number of participants: 49 patients

  • 1 transplanted patient with fibrosarcoma (included in the present review)

  • not included in the present: 48 patients with diagnoses other than NRSTS: 19x medulloblastoma, 12x glial tumors, 7x pineoblastoma, 5x ependymoma, 3x Ewing family of tumors, 2x germ cell tumor

Age: not specified

Gender: not specified

Interventions

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival

Secondary outcomes: toxicity

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Hara 2010

Methods

Duration: 2003 to 2009

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 67 months

Participants

Setting: single center in Japan

Eligibility criteria: angiosarcoma

Number of participants: 1 patient

  • 1 transplanted patient with splenic angiosarcoma (included in the present review)

Age: 48 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): ifosfamide 9000 mg/m2, etoposide 900 mg/m2, and carboplatin
1200 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Hawkins 2002

Methods

Duration: 1996 to 1998

Study design: prospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: 3 centers in the United States

Eligibility criteria: children and adolescents with metastatic sarcomas

Number of participants: 23 patients

  • 4 transplanted patients with NRSTS (included in the present review): 2x desmoplastic small round-cell tumor, 1x leiomyosarcoma, 1x fibromyxoid sarcoma

  • not included in the present: 17 patients with diagnoses other than NRSTS: 9x Ewing family of tumors, 6x rhabdomyosarcoma, 2x undifferentiated sarcoma, 1x anaplastic Wilms tumor, 1x malignant peripheral nerve sheath tumor

Age: 5 to 19 years of age

Gender: 5 male, 1 female

Interventions

High-dose chemotherapy (HDCT): vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Hoogerbrugge 1997

Methods

Duration: 2003 to 2009

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 8 months

Participants

Setting: single center in the Netherlands

Eligibility criteria: fibrosarcoma

Number of participants: 1 patient

  • 1 transplanted patient with disseminated fibrosarcoma (included in the present review)

Age: 1 year of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): etoposide 1500 mg/m2, carboplatin 1500 mg/m2 and melphalan 140 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: Amgen, Inc. (biopharmaceutical company) and Roche Inc. (pharmaceutical company) were acknowledged for their support of the study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Houet 2010

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: more than 10 years

Participants

Setting: single center in Germany

Eligibility criteria: desmoplastic small round-cell tumour

Number of participants: 1 patient

  • 1 transplanted patient with advanced intra-abdominal desmoplastic small round-cell tumour and lymph node involvement (included in the present review)

Age: 31 years of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: grants from the Deutsche Krebshilfe (nonprofit organization)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Jordan 2010

Methods

Duration: 2004 to 2006

Study design: prospective series of cases without control

Treatment: number of arms: 1

Follow-up time: 3 to 36 months

Participants

Setting: single center in Germany

Eligibility criteria: histologically confirmed metastatic sarcoma or germ cell cancer, refractory to standard chemotherapy, no prior high-dose chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of at least two and adequate hematologic, hepatic, and renal functions; exclusion criteria: newly diagnosed venous thrombosis, significant cardiovascular disease or surgery within 21 days; presence of cerebral metastases was not an exclusion criterion

Number of participants: 16 patients

  • 7 transplanted patients: 2x epitheloid sarcoma, 1x synoviaI sarcoma, 1x spindle cell sarcoma, 1x leiomyosarcoma, 1x angiosarcoma, 1x hemangiopericytoma (included in the present review)

  • not included in the present review: 5 transplanted patients: 3x osteosarcoma, 2x chondrosarcoma, 1x undifferentiated sarcoma

  • not included in the present review: 3 transplanted patients: germ cell tumor (non-seminoma)

Age: range 25 to 58 years of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): ifosfamide 9000 mg/m2, etoposide 900 mg/m2, carboplatin 900 mg/m2, and bevacizumab 7.5 to 10.0 mg/kg, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: Two authors have received compensation as a member of the scientific advisory board of Roche AG (pharmaceutical company). The remaining authors declared that they have no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kasper 2007a

Methods

Duration: 1998 to 2007

Study design: retrospective series of cases without control

Treatment: number of arms: 1

Follow-up time: 0 to 54 months (for each included case reported: 0, 2, 4, 4, 6, 11, 14, 16, 19, 20, 20, 21, 26, 54 months)

Participants

Setting: single center in Germany

Eligibility criteria: patients with bone and soft tissue sarcomas receiving high-dose chemotherapy and autologous stem cell support

Number of participants: 38 patients

  • 11 transplanted patients: 5x synoviaI sarcoma, 3x leiomyosarcoma, 2x liposarcoma 1x malignant fibrous histiocytoma (included in the present review)

  • not included in the present review: 20 transplanted patients: 10x Ewing family of tumors, 6x osteosarcoma, 1x chondrosarcoma, 3x not otherwise specified sarcoma

  • not included in the present review: 7 transplanted patients: 4x malignant peripheral nerve sheath tumors, 2x rhabdomyosarcomas, 1x meningosarcoma

Age: range 23 to 65 years of age

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): 23 patients: ifosfamide 12000 mg/m2, carboplatin 1200 mg/m2, and etoposide
1200 mg/m2, total doses; 7 patients: melphalan 420 mg/m2, busulfan 1800 mg/m2, total doses; 4 patients: melphalan 180 mg/m2 and etoposide 3000 mg/m2, total doses; 2 patients: melphalan 200 mg/m2; 2 patients: carboplatin 600 mg/m2, etoposide 600 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kasper 2010

Methods

Duration: 2003 to 2008

Study design: prospective nonrandomized controlled clinical trial

Treatment: number of arms: 2

Follow-up time: follow up was not reported; overall survival was assessed from the time of study inclusion and ranged from 0 to 34 months

Participants

Setting: single center in Germany

Eligibility criteria: primary or recurrent metastatic soft tissues sarcoma; no patients with unresectable disease were included; normal creatinine, normal cardiac function and normal bilirubin levels were required before high-dose chemotherapy

Number of participants: 34 patients

  • 9 patients had partial response to induction chemotherapy and received HDCT and autologous HSCT:

    • 4 patients had NRSTS: 2x malignant fibrous histiocytoma, 1x leiomyosarcoma, 1x synoviaI sarcoma (included in the present review)

    • not included in the present review: 5 patients had other diagnosis (56%): 3x not otherwise specified tumor, 1x primitive neuroectodermal tumor, 1x rhabdomyosarcoma

  • 25 patients received SDCT:

    • 16 patients had NRSTS

    • 9 patients with other tumors than NRSTS including including not otherwise specified tumor (36%); 1 of the 9 patients had partial response to induction chemotherapy but refused HDCT and autologous HSCT.

Age: not specified

Gender: not specified

Interventions

Arm 1:

  • High-dose chemotherapy (HDCT): ifosfamide 12000 mg/m2, carboplatin 1200 mg/m2 and etoposide 1200 mg/m2, total doses

  • Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

Arm 2:

  • Standard-dose chemotherapy: doxorubicin 75 mg/m2 and ifosfamide 6000 mg/m2, total doses

Outcomes

Primary outcomes:

  • Overall survival: aggregate data included less than 80% NRSTS patient data; individual data reported

Secondary outcomes:

  • Progression-free survival: aggregate data included less than 80% NRSTS patient dataAdverse events reported as individual data

NotesThe authors declared that they have no conflict of interest.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskComparative trial but only individual data were relevant
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kozuka 2002

Methods

Duration: 1999 to 2000

Study design: retrospective report of 2 cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in Japan

Eligibility criteria: recurrent soft tissues sarcoma

Number of participants: 2 patients

  • 2 transplanted patients: 1x malignant fibrous histiocytoma, 1x malignant hemangiopericytoma (included in the present review)

Age: 21 and 37 years of age

Gender: 2 males

Interventions

High-dose chemotherapy (HDCT): ifosfamide 15000 mg/m2, carboplatin 1200 mg/m2, and etoposide 1500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kretschmar 1996

Methods

Duration: not specified

Study design: retrospective report of 3 cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 3 patients

  • 1 transplanted patients: desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 2x desmoplastic small round-cell tumor not transplanted

Age: 13 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT)

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Krskova 2007

Methods

Duration: in 1998

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the Czech Republic

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 1 patients

  • 1 transplanted patients: synovial sarcoma (included in the present review)

Age: 9 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT)

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kurre 2000

Methods

Duration: 1994 to 1998

Study design: retrospective report of 3 cases without control

Treatment: number of arms: 1

Follow-up time: 26 and 42 months after diagnosis

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 3 patients

  • 2 transplanted patients: 2x desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 1x desmoplastic small round-cell tumor, no transplantation

Age: 5 and 2.5 years of age

Gender: 1 male and 1 female

Interventions

High-dose chemotherapy (HDCT): doxorubicin 75 mg/m2, cyclophosphamide 1800 mg/m2, ifosfamide 9000 mg/m2, and etoposide 500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kushner 1996

Methods

Duration: not specified

Study design: prospective series of cases and controls

Treatment: number of arms: 2

Follow-up time: 13 to 34 months

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 12 patients

  • 4 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 8 patients with desmoplastic small round-cell tumor that were not transplanted

Age: 10, 11, 11, and 14 years of age

Interventions

Arm 1:

Chemotherapy: cyclophosphamide 4200 mg/m2, doxorubicin 75 mg/m2, vincristine 2000 mg/m2, ifosfamide 9000 mg/m2, and etoposide 500 mg/m2, total doses

Arm 2:

Additional high-dose chemotherapy (HDCT): thiotepa 900 mg/m2 and carboplatin 1500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT):

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskControls but only individual data relevant
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kushner 2001

Methods

Duration: not specified

Study design: preliminary results of a prospective series of cases

Treatment: number of arms: 1

Follow-up time: 2 years

Participants

Setting: single center in the United States

Eligibility criteria: diagnosis of a cancer that had 25% cure rate with conventional therapies; adequate function of kidneys, heart, and liver

Number of participants: 21 patients

  • 1 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 20 transplanted patients with diagnoses other than NRSTS: 11x neuroblastoma, 3x Ewing family of tumors, 3x medulloblastoma, 1x glioblastoma multiforme, 1x astrocytoma, 1x ovarian teratoma

Age: 29 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): topotecan 10 mg/m2, thiotepa 900 mg/m2, carboplatin 1500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: This work was supported in part by grants from the National Cancer Institute (non-profit organization), the Robert Steel Foundation (non-profit organization), the Katie Find A Cure Fund (non-profit organization), and the Justin Zahn Fund (non-profit organization).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Kushner 2008

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 26 months

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 1 patient

  • 1 transplanted patient with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 1x desmoplastic small round-cell tumor, no transplantation

Age: 18 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): whole abdominal-pelvic radiation therapy 3000 Gy and irinotecan 250 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: Supported in part by grants from the National Cancer Institute (non-profit organization), Food and Drug Administration (non-profit organization), Hope St Kids (non-profit organization), Katie Find A Cure Fund (non-profit organization), and Robert Steel Foundation (non-profit organization).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Lafay-Cousin 2000

Methods

Duration: 1986 to 1998

Study design: prospective report of 18 cases without control

Treatment: number of arms: 1

Follow-up time: 8 to 31 months (for each included case 8, 13, 16, 31 months reported)

Participants

Setting: 4-center study in France

Eligibility criteria: recurrent mesenchymal tumors

Number of participants: 18 patients

  • 2 transplanted patients: 2x desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 14x transplanted patients with rhabdomyosarcoma, 2x undifferentiated sarcoma

Age: 11 and 16 years of age

Gender: 2 females

Interventions

High-dose chemotherapy (HDCT): thiotepa 900 mg/m2 total dose

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow or peripheral blood (not specified for each included case)

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Lashkari 2009

Methods

Duration: 1995 to 1999

Study design: prospective report of 13 cases without control

Treatment: number of arms: 1

Follow-up time: 99 and 138 months

Participants

Setting: single center in the United States

Eligibility criteria: locally advanced or metastatic sarcoma

Number of participants: 13 patients

  • 1 transplanted patients: 1x malignant fibrous histiocytoma, (included in the present review)

  • not included in the present review: 11x transplanted patients with diagnoses other than NRSTS: 7x Ewing family of tumors, 4x rhabdomyosarcoma, 1x undifferentiated sarcoma

Age: 40 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): doxorubicin 150 mg/m2, ifosfamide 14000 mg/m2, melphalan 150 mg/m2, cisplatin 200 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: progression-free survival reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Lippe 2003

Methods

Duration: not specified

Study design: retrospective report of 2 cases without control

Treatment: number of arms: 1

Follow-up time: 34 months after diagnosis

Participants

Setting: single center in Italy

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 2 patients

  • 1 transplanted patient with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 1x desmoplastic small round-cell tumor without transplantation

Age: 27 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): cyclophosphamide 7000 mg/m2, total dose

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Livaditi 2006

Methods

Duration: not specified

Study design: retrospective report of 5 cases without control

Treatment: number of arms: 1

Follow-up time: 11 months and 15 months

Participants

Setting: single center in Greece

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 5 patients

  • 2 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 3x desmoplastic small round-cell tumor without transplantation

Age: 7 and 13 years

Gender: 1 male and 1 female

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Madigan 2007

Methods

Duration: 1983 to 2003

Study design: retrospective report of 14 cases without control

Treatment: number of arms: 1

Follow-up time: 34 months and 104 months after diagnosis

Participants

Setting: single center in the United States

Eligibility criteria: extracranial rhabdoid tumors

Number of participants: 14 patients

  • 1 transplanted patients with extracranial, extrarenal rhabdoid tumor (included in the present review)

  • not included in the present review: 12x extracranial rhabdoid tumors without transplantation, 1x extracranial but renal rhabdoid tumor with transplantation

Age: 30 months of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Matsuzaki 2002

Methods

Duration: in 1999

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in Japan

Eligibility criteria: synovial sarcoma

Number of participants: 1 patients

  • 1 transplanted patients with synovial sarcoma (included in the present review)

Age: 11 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Mazuryk 1998

Methods

Duration: in 1996

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 19 months

Participants

Setting: single center in Canada

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 1 patient

  • 1 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

Age: 19 years of age

Gender: 1 female

Interventions

High-dose chemotherapy (HDCT): busulfan 16 mg/kg and melphalan 140 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Mingo 2005

Methods

Duration: not stated

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 12 months

Participants

Setting: single center in Spain

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 1 patient

  • 1 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

Age: 4 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): etoposide, vincristine, ifosfamide, dactinomycin, and doxorubicin

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesPrimary outcomes: overall survival reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Mitchell 1994

Methods

Duration: not specified

Study design: report of 11 cases without control, unclear if retrospective or prospective study

Treatment: number of arms: 1

Follow-up time: 6 months regarding the included patient

Unclear if retrospective or prospective study without controls in a single centre, observed in the United Kingdom; information on observation period not available

Participants

Setting: single center in the United Kingdom

Eligibility criteria: malignant disease

Number of participants: 11 patients

  • 1 transplanted patients with angiosarcoma (included in the present review)

  • not included in the present review: 5x Ewing family of tumors, 3x rhabdomyosarcoma, 1x acute myeloid leukemia, 1x T-cell lymphoma

Age: 16 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT):

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow and peripheral blood in addition

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskUnclear if retrospective and no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Navid 2006

Methods

Duration: 1996 to 2000

Study design: retrospective report of 24 cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: high-risk sarcomas

Number of participants: 24 patients

  • 2 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

  • not included in the present review: 2 patients with desmoplastic small round-cell tumor not transplanted

  • not included in the present review: 20 patients with diagnoses other than NRSTS: 11x Ewing family of tumors, 9x rhabdomyosarcoma

Age: 14 and 21 years

Gender: 2 males

Interventions

High-dose chemotherapy (HDCT): cyclophosphamide and targeted topotecan

Autologous hematopoietic stem cell transplantation (HSCT):

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Patel 2004

Methods

Duration: 1994 to 2001

Study design: prospective report of 37 cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: skeletal osteosarcoma and variant bone tumors with poor prognosis

Number of participants: 37 patients

  • 6 transplanted patients with malignant fibrous histiocytoma (included in the present review)

  • not included in the present review: 29 patients with diagnoses other than NRSTS: 29x osteosarcoma, 2x chondrosarcoma

Age: not specified

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): cisplatin 120 mg/m2, ifosfamide 10000 mg/m2, and doxorubicin 75 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival was not reported for the 6 individual cases

Secondary outcomes: toxicity reported as individual data

Notes

Financial support: not addressed

The following conclusion might not clearly substantiated by the presented data: Supplemental table 2: 14 HDCT plus autologous HSCT; 18 conventional chemotherapy. Text: "HDC seemed to delay relapse, but did not appear to prolong survival: 2-year EFS 17.9 +/- 11.3% versus 13.2 +/- 8.1%, P < 0.035 and OS 51.4 +/- 14.4% versus 50.9 +/- 11.6%, P value0.99. Two-year survival was 51.4 +/- 14.4% versus 48.6 +/- 16.7% P value 0.57 for patients treated with HDC (24 pts) versus conventional adjuvant chemotherapy (12 pts), respectively."

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Peters 1986

Methods

Duration: not specified

Study design: prospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: metastatic cancer and sarcoma

Number of participants: 29 patients

  • 2 transplanted patients with NRSTS: 1x fibrosarcoma, 1x leiomyosarcoma (included in the present review)

  • not included in the present review: 27 patients with diagnoses other than NRSTS

Age: 24 and 38 years

Gender: 2 females

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Peters 1989

Methods

Duration: not specified

Study design: prospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: metastatic cancer and sarcoma

Number of participants: 23 patients

  • 2 transplanted patients synovial sarcoma (included in the present review)

  • not included in the present review: 23 patients with diagnoses other than NRSTS

Age: 15 and 26 years

Gender: not specified

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

OutcomesSecondary outcomes: adverse events reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Philippe-Chomette 2012

Methods

Duration: 1995 to 2006

Study design: retrospective of cases without concurrent control

Treatment: number of arms: 1

Follow-up time: median of 49 months (range 9 to 108) for survivors

Participants

Setting: multicenter study in France and Belgium

Eligibility criteria: desmoplastic small round-cell tumor (DSRCT) diagnosed by the presence of the diagnostic genetic marker designated the Ewing sarcoma and Wilms tumor (EWS-WT1) fusion transcript originating at a chromosomal translocation breakpoint specific for DSRCT; patients under the age of 30 years; clinical data available

Number of participants: 14 patients

  • 14 transplanted patients (included in the present review)

Age: range (4 to 29.7 years for 38 participants)

Gender: 12 males and 2 females

Interventions

High-dose chemotherapy (HDCT): various regimens

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: overall survival as aggregate data; treatment-related mortality as individual data

Secondary outcomes: event-free survival as aggregate data; the first event of progression or relapse was taken into account for calculation of event-free survival.

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Recchia 2006

Methods

Duration: not specified

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 48 months

Participants

Setting: single center in Italy

Eligibility criteria: malignant fibrous histiocytoma

Number of participants: 1 patient

  • 1 transplanted patients with malignant fibrous histiocytoma (included in the present review)

Age: 40 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): cyclophosphamide 4500 mg/m2, carboplatin 1000 mg/m2, and etoposide 1500 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Saab 2007

Methods

Duration: not specified

Study design: retrospective report of 11 cases without control

Treatment: number of arms: 1

Follow-up time: from diagnosis

Participants

Setting: single center in the United States

Eligibility criteria: desmoplastic small round-cell tumor

Number of participants: 11 patients

  • 4 transplanted patients with desmoplastic small round-cell tumor (included in the present review)

Age: 5, 14, 18, and 21 years

Gender: 4 males

Interventions

High-dose chemotherapy (HDCT)

  • 2 patients: cyclophosphamide and topotecan

  • 1 patient: cyclophosphamide and etoposide

  • 1 patient: busulphan and melphalan

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: not specified

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: toxicity reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Slease 1988

Methods

Duration: not specified

Study design: retrospective report of cases without control

Treatment: number of arms: 1

Follow-up time: not specified

Participants

Setting: single center in the United States

Eligibility criteria: refractory malignant solid tumors

Number of participants: 26 patients

  • 3 transplanted patients: 2x malignant fibrous histiocytoma, 1x leiomyosarcoma (included in the present review)

  • not included in the present review: 23 patients with diagnoses other than NRSTS

Age: 41, 45, 47 years

Gender: 3 males

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: bone marrow

Outcomes

Primary outcomes: overall survival

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Sung 2003

Methods

Duration: 1998 to 2001

Study design: prospective report of 26 cases without control

Treatment: number of arms: 1

Follow-up time: 19, 45, and 45 months regarding the included patients

Participants

Setting: single center study in Korea

Eligibility criteria: high-risk malignant solid tumors

Number of participants: 26 patients

  • 2 transplanted patients: 1x clear cell sarcoma; 1x malignant fibrous histiocytoma (included in the present review)

  • not included in the present review: 24 patients with diagnoses other than NRSTS: 15x neuroblastoma, 3x medulloblastoma, 2x brain stem glioma, 1x glioblastoma multiforme, 1x Ewing family of tumors, 1x astrocytoma, 1x rhabdoid sarcoma, primary location not specified

Age: 20 and 48 months of age

Gender: 2 males

Interventions

High-dose chemotherapy (HDCT): successive double HDCT

  • clear cell sarcoma: melphalan, etoposide, carboplatin, total body irradiation/cyclophosphamide, etoposide

  • rhabdoid sarcoma: melphalan, etoposide, carboplatin/ifosfamide, carboplatin, etoposide

  • malignant fibrous histiocytoma: carboplatin, etoposide, melphalan/ifosfamide, carboplatin, etoposide

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskProspective but no relevant aggregate data
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Yamamura 2003

Methods

Duration: in 1996

Study design: retrospective report of a single case without control

Treatment: number of arms: 1

Follow-up time: 4 months following diagnosis

Participants

Setting: single center study in Japan

Eligibility criteria: rhabdoid sarcoma

Number of participants: 1 patient

  • 1 transplanted patients with malignant fibrous histiocytoma (included in the present review)

Age: 33 years of age

Gender: 1 male

Interventions

High-dose chemotherapy (HDCT): tandem HDCT: ifosfamide 6000 mg/m2, carboplatin 1200 mg/m2, etoposide 1200 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

Outcomes

Primary outcomes: overall survival reported as individual data

Secondary outcomes: adverse events (development of chronic myelocytic leukemia following chemotherapy) reported as individual data

NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Yonemoto 1999

Methods

Duration: in 1995

Study design: retrospective report of 3 cases without control

Treatment: number of arms: 1

Follow-up time: 6, 6, and 8 months regarding the included patients

Participants

Setting: single center study in Japan

Eligibility criteria: sarcomas

Number of participants: 10 patients

  • 3 transplanted patients with synovial sarcoma (included in the present review)

  • not included in the present review: 7 patients with diagnoses other than NRSTS: 6x Ewing family of tumors, 1x osteosarcoma

Age: 17, 28, and 40 years of age regarding the included patients

Gender: 3 males regarding the included patients

Interventions

High-dose chemotherapy (HDCT): tandem HDCT: busulfan 16 mg/kg, melphalan 140 mg/m2, thiotepa 600 mg/m2, total doses

Autologous hematopoietic stem cell transplantation (HSCT)

  • stem cell source: peripheral blood

OutcomesSecondary outcomes: adverse events reported as individual data
NotesFinancial support: not addressed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNo randomization
Allocation concealment (selection bias)High riskNo allocation concealment
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome
Selective reporting (reporting bias)Unclear riskNo protocol available
Prospective designHigh riskRetrospective
Comparable baseline characteristicsHigh riskCases without control
Assignment of patients to treatment groupsHigh riskSingle-arm study
Concurrent controlHigh riskNo control
Loss to follow-upUnclear riskPossible but not reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Abdel-Dayem 1999not intervention of interest
Abrahamsen 2000not diagnosis of interest (histological types of sarcoma not specified)
Aleinikova 2002not diagnosis of interest
Amarti 1995not intervention of interest
Antman 1990not diagnosis of interest (data not reported separately)
Arancibia 2009not diagnosis of interest (data not reported separately)
Atra 1996not diagnosis of interest
Atra 2002not diagnosis of interest
Ayash 1991not publication type of interest (review)
Baker 1987not intervention of interest
Banna 2007not publication type of interest (review)
Beaujean 1987not diagnosis of interest (data not reported separately)
Bechter 2009not publication type of interest (review)
Bien 2007not diagnosis of interest
Bokemeyer 1994anot intervention of interest
Bokemeyer 1994bnot intervention of interest
Borden 1987not intervention of interest
Borinstein 2009not intervention of interest
Bouligand 2007not diagnosis of interest
Bramwell 1986not diagnosis of interest (data not reported separately)
Bramwell 1987not intervention of interest
Brugger 1993not intervention of interest
Chandrakasan 2011not intervention of interest
Chang 1988not intervention of interest
Chen 2004not diagnosis of interest
Childs 2004not publication type of interest (review)
Chitalkar 2009not diagnosis of interest (data not reported separately)
Chuman 2000not publication type of interest (review)
Chuman 2004not diagnosis of interest (data not reported separately)
Church 2006not intervention of interest
Clamon 1983not intervention of interest
Coulibalya 2008not intervention of interest
Crist 1987not intervention of interest
Cunningham 1994not intervention of interest
Czyzewski 1999not diagnosis of interest (data not reported separately)
Dantonello 2010not diagnosis of interest (data not reported separately)
Devalck 1992not publication type of interest (review)
Duffaud 2005not diagnosis of interest
Dumontet 1992not diagnosis of interest (data not reported separately)
Edmonson 1993not intervention of interest
Ehlert 2012not diagnosis of interest (data not reported separately)
Ek 2006not publication type of interest (review)
Elias 1998not publication type of interest (review)
Endo 1996not diagnosis of interest (undifferentiated sarcoma)
Ettinghausen 1986not intervention of interest
Fayette 2009not intervention of interest
Ferrari 2005not intervention of interest (one patient with HSCT not reported separately)
Figuerres 2000not diagnosis of interest (data not reported separately)
Fine 2007not intervention of interest
Florine 1988not diagnosis of interest
Frapier 1998not diagnosis of interest (undifferentiated sarcoma)
Frustaci 2001not intervention of interest
Gadner 1992not diagnosis of interest (data not reported separately)
Gadner 2002not diagnosis of interest
Gamillscheg 1991not diagnosis of interest (data not reported separately)
Garcia-del-Muro 2011not intervention of interest
Ghavamzadeh 2011not diagnosis of interest (data not reported separately)
Gooskens 2011not diagnosis of interest
Gorin 1981not diagnosis of interest
Gortzak 2001not intervention of interest
Goto 2004not publication type of interest (review)
Gratwohl 2004anot diagnosis of interest (data not reported separately)
Gratwohl 2004bnot diagnosis of interest (data not reported separately)
Gratwohl 2006not diagnosis of interest (data not reported separately)
Gu 2004not diagnosis of interest
Halperin 1984not intervention of interest
Hara 1998not diagnosis of interest (rhabdomyosarcoma)
Harada 1982not diagnosis of interest (data not reported separately)
Hartmann 1984not diagnosis of interest
Hartmann 1997not diagnosis of interest (data not reported separately)
Hayes-Jordan 2009not publication type of interest (review)
Hayes-Jordan 2012not publication type of interest (review)
He 1999not intervention of interest
Hernandez 1999not intervention of interest
Herzog 2005not publication type of interest (review)
Hibi 1993not intervention of interest
Hoeffken 1997not diagnosis of interest (data not reported separately)
Honda 2011not diagnosis of interest
Horiuchi 2005not diagnosis of interest
Hubbard 1977not intervention of interest
Hutspardol 2012not diagnosis of interest
Ivanova 2010not diagnosis of interest (data not reported separately)
Iyer 2013not intervention of interest
Jamil 2004not diagnosis of interest (data not reported separately)
Jebson 2004not intervention of interest
Jelic 1997not intervention of interest
Kabickova 2003not diagnosis of interest (data not reported separately)
Kallianpur 2012not publication type of interest (review)
Kaminski 2000not diagnosis of interest (intracranial)
Kampe 1993not intervention of interest
Kasper 2005not publication type of interest (review)
Kasper 2006not publication type of interest (duplicate data included in follow-up paper Kasper 2008)
Katzenstein 2003not diagnosis of interest
Kingston 1984not diagnosis of interest
Kinsella 1988not diagnosis of interest (data not reported separately)
Kinugawa 1995not intervention of interest
Kiss 2009not diagnosis of interest (data not reported separately)
Klein 1983not intervention of interest
Klingebiel 2008not diagnosis of interest (data not reported separately)
Koscielniak 1997not diagnosis of interest
Koscielniak 1999not intervention of interest
Koscielniak 2002not publication type of interest (review)
Kuehne 2000not diagnosis of interest
Kushner 2000not intervention of interest (data not reported separately)
Kwon 2010not diagnosis of interest
Ladenstein 1997not diagnosis of interest (data not reported separately)
Lal 2005not intervention of interest (data not reported separately)
Lasalvia-Prisco 2012not diagnosis of interest (data not reported separately)
Le Cesne 2000not intervention of interest
Leyvraz 2006not intervention of interest
Lorigan 2007not intervention of interest
Macak 2003not intervention of interest
Makris 2009not intervention of interest
Maraninchi 1984not diagnosis of interest
Maurel 2009not intervention of interest
Mesia 1994not diagnosis of interest (undifferentiated sarcoma)
Minard-Colin 2004not intervention of interest
Mohensy 2011not intervention of interest
Mueller 2002not diagnosis of interest
Nachbaur 1994not diagnosis of interest
Nag 1995not intervention of interest (radiotherapy)
Nakamura 2008not diagnosis of interest (undifferentiated sarcoma)
Nath 2005not diagnosis of interest
Nemet 1990not diagnosis of interest
Nemet 1999not diagnosis of interest
Nickerson 2004not intervention of interest
Nieboer 2005not diagnosis of interest
Nieto 1999not publication type of interest (review)
Nieto 2004not publication type of interest (review)
Nieto 2007not diagnosis of interest (data not reported separately)
Ninomiya 1988not diagnosis of interest (data not reported separately)
Nivison-Smith 2005not diagnosis of interest (data not reported separately)
Odile 2008not intervention of interest
Ortega 1991not diagnosis of interest
Oue 2010not diagnosis of interest
Ozkaynak 2008not diagnosis of interest
Palumbo 1997not intervention of interest
Pasetto 2003not publication type of interest (review)
Passweg 2012not outcome of interest
Patel 1992not publication type of interest (review)
Patel 1998not intervention of interest
Perez-Gracia 2001not diagnosis of interest (data not reported separately)
Perez-Martinez 2003not intervention of interest
Perez-Martinez 2011not intervention of interest
Pick 1988not publication type of interest (review)
Pinkerton 1991not diagnosis of interest
Pohlodek 1994not outcome of interest
Radulescu 2008not diagnosis of interest
Rapidis 2008not publication type of interest (review)
Ray-Coquard 2001not publication type of interest (review)
Reichardt 1998not intervention of interest
Rich 1980not diagnosis of interest
Ronghe 2004not diagnosis of interest (rhabdoid tumor without information about localisation)
Rupolo 2001not intervention of interest
Rzepecki 2006not diagnosis of interest (data not reported separately)
Samma 1994not diagnosis of interest
Sano 2012not intervention of interest
Santoro 1995not diagnosis of interest
Sawyer 1999not publication type of interest (review)
Schellong 1981not publication type of interest (review)
Schilder 1999not diagnosis of interest
Schilder 2001not diagnosis of interest
Schimmer 2002not diagnosis of interest (data not reported separately)
Schlegel 2009not intervention of interest
Schlemmer 2006not diagnosis of interest (data not reported separately)
Schuster 2008not diagnosis of interest (data not reported separately)
Schwartzberg 1993not diagnosis of interest
Schwella 1998not diagnosis of interest (data not reported separately)
Seibel 2004not intervention of interest
Seynaeve 1999not publication type of interest (review)
Shaw 1996not diagnosis of interest (undifferentiated sarcoma; rhabdoid tumor without information about localisation)
Shen 1993not diagnosis of interest
Shenoy 2010not diagnosis of interest
Shvarova 2009not intervention of interest
Slovacek 2007not publication type of interest (review)
Somers 2006not diagnosis of interest (histologic type not specified for individual data)
Sudo 1991not intervention of interest
Tajima 1983not diagnosis of interest
Tajima 1988not diagnosis of interest
Takeda 1995not disease of interest
Taskinen 1998not diagnosis of interest
Termuhlen 2006not disease of interest
Tursz 1996not intervention of interest
Unruh 1979not intervention of interest
Van Glabbeke 1993not intervention of interest
Verma 2002not publication type of interest (review)
Verma 2008anot publication type of interest (systematic review)
Verma 2008bnot publication type of interest (review)
Verweij 2000not intervention of interest
Walker 2004not intervention of interest
Watanabe 2006not diagnosis of interest (rhabdoid tumor without information about localisation)
Webber 2007not intervention of interest
Weh 1996not intervention of interest
Woods 1999not publication type of interest (review)
Yamada 1999not diagnosis of interest
Yaqoob 2006not publication type of interest (review)
Yeung 1994not diagnosis of interest
Yokoyama 1993not intervention of interest
Yumura-Yagi 1998not diagnosis of interest
Zoubek 1994not intervention of interest

Characteristics of ongoing studies [ordered by study ID]

NCT00002601

Trial name or title

Title: Combination chemotherapy and peripheral stem cell transplantation in treating patients with sarcoma

Official Title: High-dose doxorubicin and ifosfamide followed by melphalan and cisplatin for patients with high-risk and recurrent sarcoma

Methods

Study start date: September 1994

Estimated primary completion date: March 2013

Study design: Intervention model: single group assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 1

Follow-up time: 2 years after completion of treatment

Participants

Setting: single center in the United States: City of Hope

Eligibility criteria: 10 to 55 years of age; patients with high risk or advanced soft tissue sarcoma, osteosarcoma, Ewing family of tumors, or rhabdomyosarcoma; Karnofsky performance status 80% to 100%; other criteria apply

Estimated enrollment: 20 patients

Interventions

High-dose chemotherapy (HDCT): cisplatin, doxorubicin, ifosfamide, melphalan

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

OutcomesOverall survival, disease-free survival, response, toxicity, feasibility of administration of 2 cycles of high-dose chemotherapy followed by autologous HSCT
Starting date

September 1994

This study is ongoing, but not recruiting participants

Contact informationStudy chair: George Somlo, MD, City of Hope, Beckman Research Institute, Duarte, California, United States
NotesFinancial support: non-profit organization

NCT00002854

Trial name or title

Title: High-dose combination chemotherapy plus peripheral stem cell transplantation in treating patients with advanced cancer

Official Title: Phase I pilot study of sequential high-dose cycles of cisplatin, cyclophosphamide, etoposide and ifosfamide, carboplatin and taxol with autologous stem cell support

Methods

Study start date: December 1994

Estimated primary completion date: February 2013

Study design: Intervention model: single group assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 1

Follow-up time: for at least 5 years after completion of treatment

Participants

Setting: single center in the United States: City of Hope

Eligibility criteria: 18 to 55 years of age; patients with primary soft tissue sarcoma with high-grade disease greater than 10 cm or that is metastatic, osteosarcoma, breast carcinoma, ovarian cancer, malignant melanoma, metastaticsmall cell bone carcinoma, metastaticEwing family of tumors, metastaticgastrointestinal malignancy or recurrent Wilms tumor; Karnofsky performance status 80% to 100%; other criteria apply

Estimated enrollment: 6 patients

Interventions

High-dose chemotherapy (HDCT): cisplatin, cyclophosphamide, etoposide and ifosfamide, carboplatin and taxol

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

OutcomesToxicity, feasibility of administration of 2 cycles of high-dose chemotherapy followed by autologous HSCT
Starting date

September 1994

This study is ongoing, but not recruiting participants

Contact informationStudy chair: George Somlo, MD, City of Hope, Beckman Research Institute, Duarte, California, United States
NotesFinancial support: non-profit organization

NCT00141765

Trial name or title

Title: Study of high-dose chemotherapy with bone marrow or stem cell transplant for rare poor-prognosis cancers

Official Title: High-dose doxorubicin and ifosfamide followed by melphalan and cisplatin for patients with high-risk and recurrent sarcoma

Methods

Study start date: January 1997

Estimated primary completion date: January 2014

Study design: Intervention model: single group assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 1

Follow-up time: 1 year after completion of treatment

Participants

Setting: single center in the United States: The University of Michigan

Eligibility criteria: 21 years old or younger, histologically-confirmed Wilms tumor, liver cancer, recurrent brain tumor of childhood, nasopharyngeal carcinoma, fibrosarcoma, desmoplastic small round cell tumor, germ cell tumor or other small round cell tumor, which: is metastatic and has <25% cure rate with conventional treatment or progressed after prior chemotherapy and has <25% salvage rate with non-myeloablative therapies; other criteria apply

Estimated enrollment: not stated

Interventions

High-dose chemotherapy (HDCT): cyclophosphamide, ifosfamide, carboplatin and thiotepa

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

OutcomesDisease-free survival
Starting date

January 1997

This study is ongoing, but not recruiting participants

Contact informationPrincipal investigator: John E Levine, MS MD, The University of Michigan, Ann Arbor, Michigan, United States
NotesFinancial support: non-profit organization

NCT00623077

Trial name or title

Title: Total marrow irradiation added to an alkylator-intense conditioning regimen for patients with high risk or relapsed solid tumors

Official Title: Dose escalation of total marrow irradiation added to an alkylator-intense conditioning regimen for patients with high risk or relapsed solid tumors

Methods

Study start date: August 2005

Estimated primary completion date: June 2014

Study design: Endpoint classification: safety/efficacy study; Intervention model: single group assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 1

Follow-up time: not stated

Participants

Setting: single center in the United States: University of Minnesota, Masonic Cancer Center

Eligibility criteria: up to 70 years; patients with high risk or relapsed malignancies that include: Ewing family of tumors, Wilms tumor, clear cell sarcoma, rhabdoid tumor, hepatoblastoma, rhabdomyosarcoma, soft tissue sarcoma, primary malignant brain neoplasm, retinoblastoma; other criteria apply

Estimated enrollment: 45 patients

Interventions

Total marrow irradiation with tomotherapy

High-dose chemotherapy (HDCT): busulfan, melphalan, thiotepa

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

Outcomes

Primary Outcome Measures: Maximum tolerated dose of tomotherapy up to 12 Gy

Secondary Outcome Measures: Overall survival, disease-free survival, rate of treatment-related mortality

Starting date

August 2005

This study is ongoing, but not recruiting participants

Contact informationPrincipal investigator: Michael R Verneris, MD, University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, United States
NotesFinancial support: non-profit organization

NCT00638898

Trial name or title

Title: Busulfan, melphalan, topotecan hydrochloride, and a stem cell transplant in treating patients with newly diagnosed or relapsed solid tumor

Official Title: Pilot study of high-dose chemotherapy with busulfan, melphalan, and topotecan followed by autologous hematopoietic stem cell transplant in advanced stage and recurrent tumors

Methods

Study start date: December 2006

Estimated primary completion date: April 2019

Study design: Endpoint classification: efficacy study; Intervention model: single group assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 1

Follow-up time: After completion of study treatment, patients are followed every 3 months for 1 year and then annually thereafter

Participants

Setting: single center in the United States: City of Hope

Eligibility criteria: up to 70 years; patients with relapsed neuroblastoma, rhabdomyosarcoma, Ewing family of tumor, brain tumor, soft tissue sarcomas Wilms tumor, germ cell tumor or other solid tumor who achieved at least partial response to chemotherapy, surgery, or radiotherapy; other criteria apply

Estimated enrollment: 25 patients

Interventions

High-dose chemotherapy (HDCT): busulfan, melphalan, topotecan

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

Outcomes

Primary Outcome Measures: Treatment feasibility in terms of investigational agent-related adverse events of a novel treatment combination followed by peripheral blood stem cell rescue

Secondary Outcome Measures: Overall survival, disease-free survival, Incidence of myeloid and platelet engraftment

Starting date

December 2006

This study is currently recruiting participants

Contact informationPrincipal investigator: Anna Pawlowska, MD, City of Hope, Duarte, California, United States
NotesFinancial support: non-profit organization

NCT01288573

Trial name or title

Title: A combined study in pediatric cancer patients for dose ranging and efficacy/safety of plerixafor plus standard regimens for mobilization versus standard regimens alone

Official Title: A phase 1/2 combined dose ranging and randomized, open-label, comparative study of the efficacy and safety of plerixafor in addition to standard regimens for mobilization of haematopoietic stem cells into peripheral blood, and subsequent collection by apheresis, versus standard mobilization regimens alone in pediatric patients, aged 2 to <18 years, with solid tumours eligible for autologous transplants

Methods

Study start date: February 2011

Estimated primary completion date: May 2017

Study design: Allocation: randomized; Endpoint classification: safety/efficacy study; Intervention model: parallel assignment; Masking: open label; Primary purpose: treatment

Treatment: number of arms: 2

Follow-up time: up to 24 months after completion of study treatment

Participants

Setting: multicenter trial in France, Germany, Italy, and the United Kingdom

Eligibility criteria: 2 to 18 years of age; patients with Ewing family of tumor, soft tissue sarcoma, neuroblastoma, brain tumors or other malignancy (excluding any form of leukemia) requiring treatment with high dose chemotherapy and autologous transplant as rescue therapy; other criteria apply

Estimated enrollment: 67 patients

Interventions

High-dose chemotherapy (HDCT): not specified

Autologous hematopoietic stem cell transplantation (HSCT): stem cell source: peripheral blood

Outcomes

Primary Outcome Measures: Proportion of patients achieving at least a doubling of peripheral blood CD34+ count during Stage 2

Secondary Outcome Measures: Survival rates

Starting date

February 2011

This study is currently recruiting participants

Contact informationStudy director: Medical Monitor, Genzyme Corporation (sponsor of the trial)
NotesFinancial support: Genzyme Corporation (biotechnology company)