Integration of Circulating Tumor DNA and Metabolic Parameters on ¹⁸F‐Fludeoxyglucose Positron Emission Tomography for Outcome Prediction in Unresectable Locally Advanced Non‐Small Cell Lung Cancer

This prospective study explores the prognostic value of circulating tumor DNA (ctDNA) and positron emission tomography/computed tomograpy (PET/CT) in unresectable locally advanced non-small cell lung cancer (LA-NSCLC) treated with definitive chemoradiotherapy (CRT). The discovery set includes 62 patients, with 62 baseline and 53 post-CRT plasma samples. PET/CT is performed at baseline, and 33 patients undergo mid-treatment scans after 40 Gy. Baseline ctDNA is detected in 71.0% of patients. Pre-treatment ctDNA concentration correlates with total metabolic tumor volume (TMTV) (p < 0.001) and total lesion glycolysis (TLG) (p = 0.001) but not treatment response or survival. However, patients with undetectable ctDNA and low TMTV show significantly longer progression-free survival (PFS) (34.2 vs 10.1 months, p = 0.027). Post-CRT, ctDNA is detected in 47.2% of patients, while ctDNA concentration (p = 0.005) and variant allele frequency (VAF) (p = 0.005) significantly decline. Undetectable post-CRT ctDNA associates with longer PFS (p < 0.001) and overall survival (OS) (p = 0.001). Higher ∆TMTV correlates with improved PFS and OS. Similar findings were obtained in a test of 19 patients. These results highlight post-CRT ctDNA and ∆TMTV as robust prognostic markers, potentially identifying patients who may forgo ICI consolidation.