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: people 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; participants had received no prior chemotherapy or concurrent therapy Exclusions: people for whom it was possible to perform potentially curative locoregional treatments and people with uterine, bone, or digestive tumors Number of participants: 264 participants pre‐enrolled; 207 participants received first 4 of 6 chemotherapy courses: 87 participants were randomized: tumor entities listed in Table 2 41 participants were randomized to the HDCT + autologous HSCT arm 46 participants were randomized to the SDCT arm 4 participants were not included in the analysis 3 participants of the HDCT + autologous HSCT arm 1 participant of the SDCT arm 83 participants were included in a modified (removal of 4 ineligible participants) intention‐to‐treat analysis with respect to overall survival and progression‐free survival 38 participants of the HDCT + autologous HSCT arm 45 participants of the SDCT arm 62 participants received the assigned treatment and were included in the toxicity analysis 22 participants of the HDCT + autologous HSCT arm 40 participants of the SDCT arm Age HDCT + autologous HSCT arm: median 45.8 years (range 18.5 to 65.0) SDCT arm: median 43.3 years (range 18.7 to 65.0) Gender HDCT + autologous HSCT arm: 58.5% (24/41) males; 41.5% (15/41) females SDCT arm: 50% (23/46) males; 50% (23/46) females
Interventions	All participants received 5 courses of SDCT: doxorubicin 60 mg/m2, ifosfamide 7500 mg/m2, dacarbazine 900 mg/m2, total doses; the 6th course was different between HDCT + autologous HSCT arm and SDCT arm: HDCT + autologous HSCT arm, 6th course: HDCT: ifosfamide 10,000 mg/m2, carboplatin, and etoposide 1200 mg/m2, total doses autologous HSCT: stem cell source: peripheral blood actually 22‐41 randomized participants received HDCT followed by HSCT SDCT arm, 6th course: SDCT: doxorubicin 60 mg/m2, ifosfamide 7500 mg/m2, dacarbazine 900 mg/m2, total doses actually 40/46 randomized participants received SDCT
Outcomes	Primary outcomes as defined by the study Overall survival Secondary outcomes as defined by the study Progression‐free survival Adverse effects Complete remission
Notes	Financial support: Programme Hospitalier de Recherche Clinique, French Health Ministry (nonprofit organization); French National Federation for Comprehensive Cancer Centers (nonprofit organization). Information about the histologic type of sarcoma designated as "Others" in the article were communicated by personal contact with the first author and listed in Table 2.
Risk of bias
Bias	Authors' judgement	Support 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". We assumed an adequate random sequence generation and judged at low risk of bias.
Allocation concealment (selection bias)	Unclear risk	Allocation was carried out centrally, though masking of allocation was not described in full detail. We assumed an adequate allocation concealment. However, we missed a clarifying statement. Therefore, we judged at unclear risk of bias.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Not reported; very likely not possible and not relevant for the reported outcomes of overall survival, treatment‐related mortality, and progression‐free survival. Blinding of participants has no influence on overall survival and treatment‐related mortality, which are defined as primary outcomes of the present review. Therefore, we judged at low risk of bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not reported; very likely not possible and not relevant for the reported outcomes overall survival, treatment‐related mortality, and progression‐free survival. The study was denoted as an "open, multicenter, randomized phase III study". Blinding of outcome assessment has no influence on overall survival and treatment‐related mortality, which are defined as primary outcomes of the present review. Therefore, we judged at low risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	At 36 months from randomization (HDCT versus SDCT), 51 participants had died (24 versus 27) and 25 were at risk (8 versus 17). Of 83 participants (38 versus 45) included in the modified intention‐to‐treat survival analysis, 76 participants (32 versus 44) are accounted for but 7 participants (6 versus 1) may not be explained. The number of participants with missing information was small. The potential influence of this missing information was unclear, therefore we judged at unclear risk of bias. Figure 1 of Bui‐Nguyen 2012 showed that 41 participants were randomized to the HDCT arm, but 22 participants actually received high dose and were evaluated. Figure 1 also showed that 46 participants were randomized to the SDCT arm, but 40 participants actually received standard dose and were evaluated. The potential influence of this missing information was unclear, therefore we judged atn unclear risk of bias. Table 2 of Bui‐Nguyen 2012 showed WHO grades 3/4 toxicity for all randomized participants, 22 in the HDCT arm and 51 in the SDCT arm. There was an inconsistency concerning the number of randomized and evaluated participants between Figure 1 and Table 2. It appeared conflicting that 51 participants were reported to be randomized to the SDCT arm in Table 2, although, according to Figure 1, only 46 participants were randomized and only 40 participants actually received SDCT. Thus, instead of 51 participants, it appeared that only 40 participants were actually eligible to evaluate adverse events after SDCT.
Selective reporting (reporting bias)	Low risk	We did not identify any selective outcome reporting.
Other bias	Unclear risk	The US Food and Drug Administration sent a warning letter (Reference 15‐HFD‐45‐05‐01) addressed to the first author on 4 May 2015 to inform of objectionable conditions observed during an inspection at the clinical site between 17 and 19 September 2014 (FDA 2015). The inspection happened after the conclusion of the study included in the present review and may not have been related to the risk of bias. The potential influence of this information was unclear, therefore we judged it at unclear risk of bias.

HDCT: high‐dose chemotherapy; HSCT: hematopoietic stem cell transplantation; SDCT: standard‐dose chemotherapy; WHO: World Health Organization.