Reporting Matters: Severe Adverse Events in Soft Tissue Sarcoma Therapy-A 30-Year Systematic Review of Placebo- and...

Background: Systemic therapy for soft tissue sarcoma (STS) provides modest survival benefit but carries clinically relevant toxicity. Published trials report adverse events (AEs) of varying quality and extension. Poor toxicity reporting hampers balanced risk-benefit appraisal. Methods: A PRISMA-2020 systematic review was registered in PROSPERO CRD420251087366. PubMed, CENTRAL, and Google Scholar were searched from 16 December 2024 to 16 April 2025 for randomized controlled trials (RCTs) evaluating chemotherapy, kinase inhibitors, or immune checkpoint inhibitors in STS. AE terms were harmonized to CTCAE v5.0; event rates were normalized to patients evaluable for safety. Pooled proportions used DerSimonian-Laird random-effects models; between-group comparisons employed unpaired t-tests. Risk of bias (RoB 2) was assessed with the Cochrane RoB 2 tool. Results: Ten RCTs (1079 treated, 979 control patients; 1994-2024) met the inclusion criteria, although two lacked sufficient presentation of toxicity data and seven failed to report parallel control-arm AEs. Pooled normalized incidences for treated patients were as follows: grade ≥ 3 hematological AEs, 17% (95% CI 14-20); severe gastrointestinal AEs, 9% (8-11); and grade 4 AEs, ≤6%. Anthracycline-based and kinase-inhibitor regimens displayed comparable composite grade ≥ 3 burdens (58% vs. 84%, p = 0.64). Between-study heterogeneity was considerable for gastrointestinal and hematological events (I² > 60%), driven by differing AE scales and denominators. Late-effect toxicities (cardiac, hepatic, neurological, and nephrological) were rarely reported, occurring in <1% of the patients. Across the three RCTs with control-arm data, experimental therapy increased common grade 3 AEs by 4-12 percentage points (p = 0.001). RoB 2 flagged serious concerns in 4/10 trials. Conclusions: Severe AEs in STS systemic therapy are moderately frequent; while the toxicity spectrum differs across drug classes (e.g., hematological for anthracyclines vs. neuropathic or fatigue-related for agents such as eribulin), the aggregate burden of severe AEs has not been lower for newer agents. Confidence in these estimates is limited by incomplete and non-standardized AE reporting. Future sarcoma trials must adopt CTCAE v5.0, specify explicit safety denominators, and publish full AE matrices to enable high-certainty risk-benefit assessment.