Autologous hematopoietic stem cell transplantation following high‐dose chemotherapy for nonrhabdomyosarcoma soft tissue sarcomas
Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In people 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.
To assess the efficacy and safety of high‐dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) for all stages of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults.
For this update, we revised the search strategy to improve the precision and reduce the number of irrelevant hits. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), PubMed from 2012 to 6 September 2016, and Embase from 2012 to 26 September 2016. We searched online trial registries and congress proceedings from 2012 to 26 September 2016.
Terms representing STS and autologous HSCT were required in the title or abstract. We restricted the study design to RCTs. We included studies if at least 80% of participants had a diagnosis listed in any version of the World Health Organization (WHO) classification and classified as malignant. The search included children and adults with no age limits.
Data collection and analysis
We used standard methodologic procedures expected by Cochrane. The primary outcomes were overall survival and treatment‐related mortality.
We identified 1549 records; 85 items from electronic databases, 45 from study registries, and 1419 from congress proceedings. The revised search strategy did not identify any additional RCTs. In the previous version of the review, we identified one RCT comparing HDCT followed by autologous HSCT versus standard‐dose chemotherapy (SDCT). The trial randomized 87 participants who were considerably heterogeneous with respect to 19 different tumor entities. The data from 83 participants were available for analysis.
In the single included trial, overall survival at three years was 32.7% in the HDCT arm versus 49.4% in the SDCT arm and there was no difference between the treatment groups (hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.70 to 2.29, P = 0.44; 1 study, 83 participants; high quality evidence). In a subgroup of participants who had a complete response before HDCT, overall survival was higher in both treatment groups and overall survival at three years was 42.8% in the HDCT arm versus 83.9% in the SDCT arm and favored the SDCT group (HR 2.92, 95% CI 1.1 to 7.6, P = 0.028; 1 study, 39 participants).
In the single included trial, the authors reported one treatment‐related leukemia death two years after HDCT. They also evaluated severe adverse events WHO grade 3 to 4 in 22 participants in the HDCT arm and in 51 participants in the SDCT arm. The authors reported 11 events concerning digestive‐, infection‐, pain‐, or asthenia‐related toxicity in the HDCT arm and one event in the SDCT arm (moderate quality evidence). The development of secondary neoplasia was not addressed. We judged the study to have an overall unclear risk of bias as three of seven items had unclear and four items had low risk of bias. For GRADE, we judged three items as high quality and three items were not reported.
The limited data of a single RCT with an unclear risk of bias and moderate to high quality evidence showed no survival advantage for HDCT. If this treatment is offered it should only be given after careful consideration on an individual person basis and possibly only as part of a well‐designed RCT.
Frank Peinemann, Heike Enk, Lesley A Smith
Plain language summary
High‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation for nonrhabdomyosarcoma soft tissue sarcomas
We reviewed the evidence about the effect of high‐dose chemotherapy (medicines to kill the cancer) followed by autologous hematopoietic stem cell transplantation compared to standard‐dose chemotherapy on overall survival (time from cancer diagnosis, or treatment, to death from any cause) in people with nonrhabdomyosarcoma soft tissue sarcomas. We found one randomized controlled trial (RCT; a clinical study where people are randomly put into one of two or more treatment groups) comparing both treatments.
Nonrhabdomyosarcoma soft tissue sarcomas are a group of rare cancers. People with inoperable (cannot be removed during an operation) or metastatic (where the cancer has spread to other parts of the body) disease have a poor prognosis (outcome). It was believed that higher doses of chemotherapy might improve people's survival. However, high doses of chemotherapy stop the production of blood cells in the bone marrow and can be harmful. Stem cells (cells that can form into many cell types) collected from people before high‐dose chemotherapy can be transplanted back to the person if the blood cell count gets too low; this is called autologous hematopoietic stem cell transplantation. Due to a lack of research studies, it has not been proven that people treated like this live any longer than people 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.
The evidence is current to 6 September 2016. We found one RCT that compared 38 people in the high‐dose chemotherapy and transplantation group versus 45 people in the chemotherapy‐only group and was judged to have mainly a low risk of bias (as it was well designed). The participants were 18 to 65 years old, had various types of nonrhabdomyosarcoma soft tissue sarcomas and were monitored for about 55 months. The treatment period ranged from 2000 to 2008. The single RCT was funded by a nonprofit organization (the funder did not benefit if the trial found good results).
The results of the RCT did not favor either of the two treatment arms with respect to overall survival. There was one death related to treatment in the transplantation group and none in the chemotherapy‐only group. There were eight cases of severe nonhematologic (not related to the blood) side effects in the transplantation group and one in the chemotherapy‐only group.
Quality of evidence
The overall quality of the data was unclear and based on only one RCT. Currently, research evidence is limited for the use of high‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation for people with non‐rhabdomyosarcoma soft tissue sarcomas. Further evidence is needed through well‐designed clinical trials.
Frank Peinemann, Heike Enk, Lesley A Smith
Implications for practice
The evidence base does not support the use of high‐dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in high‐risk people with non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS). If this treatment is offered, it should only be after careful consideration on an individual person basis and possibly only as part of a well‐designed randomized controlled trial (RCT).
Implications for research
It is doubtful whether further studies are necessary to clarify the relevance of HDCT followed by autologous HSCT in people with NRSTS. However, if appropriate, any future studies would need to be methodologically well‐designed RCTs with a low risk of bias as nonrandomized studies are not beneficial in addressing this topic. Criteria for the included tumor types in any future trial should adhere to the WHO classification.