Safety Profiles and Adverse Events of Targeted Radioisotope Therapy: A Systematic Review and Meta-Analysis of Toxicity Outcomes (2015–2026)

The rapid expansion of targeted radioisotope therapy (TRT) in oncology—now encompassing six major agents including Lu-177 DOTATATE (Lutathera), Lu-177 PSMA-617 (Pluvicto), Ra-223 (Xofigo), Ac-225, I-131, and Y-90—has outpaced the development of comprehensive, cross-agent safety syntheses capable of informing clinical decision-making. Individual pivotal trials have characterized agent-specific toxicities, yet no study has systematically integrated clinical trial evidence with post-marketing surveillance data to quantify comparative safety profiles across the TRT class. The purpose of this systematic review and meta-analysis was to quantify pooled incidence rates of Grade 3–4 adverse events stratified by organ system, establish dose-response relationships between cumulative administered activity and toxicity, and compare safety profiles across six TRT agents through frequentist network meta-analysis, integrating data from the FDA Adverse Event Reporting System (FAERS) and EudraVigilance. Following PRISMA 2020 guidelines, data were retrieved from PubMed, Cochrane CENTRAL, Embase, ClinicalTrials.gov, FAERS, and EudraVigilance. Freeman-Tukey double arcsine transformation with DerSimonian-Laird random-effects models was employed for meta-analysis of proportions, supplemented by dose-response meta-regression and frequentist network meta-analysis. The analysis encompassed 2,082 registered trials, 94,015 adverse event rows from 304 trials with posted results, 27,502 FAERS reports, and 6,506 EudraVigilance individual case safety reports across 2,570 PubMed-indexed publications. Hematologic toxicity emerged as the predominant safety concern across all agents, with pooled incidence rates ranging from 70.3% (Xofigo) to 97.6% (Ac-225). Agent-specific toxicity signatures were identified: xerostomia was markedly elevated with PSMA-targeted agents (Pluvicto 59.3%, Ac-225 67.5%), while Xofigo demonstrated the most favorable overall safety profile (average pooled toxicity rate: 46.0%) compared to Ac-225 (77.4%). Post-marketing pharmacovigilance revealed significant disproportionality signals, including Y-90 leukopenia (PRR = 13.5, 95% CI: 11.56–15.84) and Xofigo anaemia (PRR = 3.2, 95% CI: 2.83–3.71). Dose-response meta-regression confirmed dose-dependent toxicity patterns supporting personalized dosimetry approaches. Significant publication bias was detected (Egger’s test p < 0.001), and substantial heterogeneity (I² > 85%) was observed across most pooled estimates. Network meta-analysis geometry identified five direct comparison pairs. This study represents the first comprehensive cross-agent safety synthesis for TRT, providing quantified evidence to support personalized dosimetry, inform clinical monitoring protocols, guide patient selection, and strengthen post-marketing regulatory surveillance.