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.