Effectiveness of Systemic Treatments in Patients with Unresectable, Advanced, or Recurrent Soft Tissue Sarcomas Previously Treated with Anthracycline-Based Therapy: A Systematic Review and Network Meta-Analysis

Introduction: Soft tissue sarcomas (STS) are rare malignancies with diverse histological subtypes and an incidence of approximately 40 cases per million annually. Although several agents, including pazopanib, trabectedin, and eribulin, have been approved in Japan since 2012 for patients previously treated with anthracyclines, clinical guidelines provide no consistent recommendations regarding second-line regimens. Given the lack of head-to-head evidence, treatment selection largely depends on clinician discretion. This study aims to evaluate the comparative efficacy of second-line or later pharmacological regimens for unresectable, advanced, or recurrent STS through a systematic review and network meta-analysis (NMA). Methods and analysis: Randomized controlled trials (RCTs), including multi-arm designs, will be identified through comprehensive searches of MEDLINE (via PubMed), Embase (via ProQuest), CENTRAL, WHO ICTRP, and ClinicalTrials.gov from inception to the search date, without language restrictions. Two reviewers will independently screen records, extract data, and assess risk of bias using the Cochrane RoB 2 tool; discrepancies will be resolved by a third reviewer. Pairwise meta-analyses will be performed using random-effects models, followed by a frequentist NMA with between-study variance estimated by REML. Consistency will be assessed using design-by-treatment interaction models (global) and node-splitting methods (local). Treatment ranking will be evaluated using P-scores or SUCRA. Certainty of evidence for each outcome will be assessed using CINeMA in line with the GRADE framework. Support/ Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Ethics and dissemination: This systematic review and network meta-analysis will be conducted using data extracted from previously published studies and trial registries. As no individual patient data will be collected or used, ethical approval is not required. The findings of this review will be disseminated through publication in a peer-reviewed journal and presentation at relevant scientific conferences. The results will also be shared with clinicians, policymakers, and researchers to inform clinical practice and future research. The final dataset and analytic code may be made available in an open-access repository to ensure transparency and reproducibility. PROSPERO Registration number: CRD420251156600 Keywords: Soft Tissue Sarcoma; Second-line Therapy; Salvage Therapy; Network Meta-Analysis; Randomized Controlled Trials