Wajahat Mirza, Khalid Hussain, Adeel Anwaar, Abdullah Shaikh, Muhammad Faizan Sajid, Wajiha Irfan, Rao Nouman Ali
ctDNA-guided or ctDNA-stratified adjuvant immunotherapy after radical surgery was associated with improved disease-free and overall survival without a statistically significant pooled increase in major toxicities. ctDNA is a promising tool for residual molecular disease that may inform postoperative immunotherapy selection; however, current evidence remains insufficient to establish ctDNA-guided selection as a definitive standard of care. Implementation should remain linked to validated assay platforms, patient fitness assessment, and individualized shared decision-making.
BACKGROUND: Adjuvant immunotherapy after radical surgery for muscle-invasive urothelial carcinoma has produced heterogeneous trial-level results, partly because clinicopathological risk factors do not completely identify patients with molecular residual disease (MRD). Circulating tumor DNA may refine postoperative treatment selection by distinguishing patients who are most likely to benefit from immune checkpoint inhibition from those who may experience unnecessary toxicity.
METHODS: This systematic review and meta-analysis was conducted according to the for Systematic Reviews and Preferred Reporting Items Meta-Analyses 2020 guidelines. PubMed/MEDLINE, Embase, and Scopus were searched from their inception until May 2026. Prospective comparative studies evaluating ctDNA-guided or ctDNA-stratified adjuvant immunotherapy versus observation or placebo after radical surgery for muscle-invasive urothelial carcinoma were included. Hazard ratios were pooled for time-to-event outcomes using generic inverse variance models, and risk ratios were pooled for dichotomous safety outcomes using Mantel-Haenszel random-effects models. The risk of bias was assessed using ROB2, and the certainty of evidence was evaluated using GRADE.
RESULTS: Five reports representing three independent randomized trial datasets were included. The ctDNA-defined efficacy population included 310 patients receiving adjuvant immunotherapy and 208 receiving observation or placebo, whereas the pooled safety analysis included 632 and 529 patients, respectively. ctDNA-guided or ctDNA-stratified adjuvant immunotherapy significantly improved disease-free survival (HR 0.46, 95% CI 0.32-0.66; P < 0.0001; I²=38%) and overall survival (HR 0.56, 95% CI 0.44-0.72; P < 0.00001; I²=0%). Any-grade adverse events were not significantly increased (RR 1.05, 95% CI 0.98-1.12), nor were grade ≥ 3/3-4 adverse events (RR 1.44, 95% CI 0.98-2.11) or serious adverse events (RR 1.25, 95% CI 0.87-1.80).
CONCLUSIONS: ctDNA-guided or ctDNA-stratified adjuvant immunotherapy after radical surgery was associated with improved disease-free and overall survival without a statistically significant pooled increase in major toxicities. ctDNA is a promising tool for residual molecular disease that may inform postoperative immunotherapy selection; however, current evidence remains insufficient to establish ctDNA-guided selection as a definitive standard of care. Implementation should remain linked to validated assay platforms, patient fitness assessment, and individualized shared decision-making.
CLINICAL TRIAL REGISTRATION: Not applicable. This study was not a clinical trial.