The Value of no Evidence of Disease (NED) in Intermediate‐Stage Hepatocellular Carcinoma After TACE: A Real‐World Study

ABSTRACT Background and Aims One‐third of patients with intermediate‐stage hepatocellular carcinoma (HCC) can achieve imaging‐based no evidence of disease (NED) during treatment after transarterial chemoembolization (TACE) and sequential therapies; however, its temporal dynamics, contributing factors and prognostic value remain unknown. Methods The longitudinal data of 1665 intermediate‐stage HCC patients from Sun Yat‐sen University Cancer Center were included as a derivation cohort; 414 patients from three external medical centers served as the validation cohort. Image‐Only NED is defined as no evidence of disease based on imaging exams while having a serum level of alpha‐fetoprotein (AFP) above the upper limit; Image‐Bio NED pertains to an additional achievement of a normal level of AFP. A semi‐Markov multistate model was adopted to identify the transitions between intermediate states, which included NED unreached, Image‐Only NED, Image‐Bio NED, recurrence after NED and death. A time‐dependent Cox proportional hazards model for overall survival (OS) was utilised to evaluate the dynamic prognostic value of NED states. Results The percentage of patients who reached Image NED and Image‐Bio NED was 35.2% and 24.7% in the derivation cohort, and 37.4% and 31.4% in the validation cohort. The proportion of Image‐Only NED and Image‐Bio NED peaked by the end of the second year since initial treatment and declined gradually. Patients with Image‐Only NED had a higher risk of recurrence compared to the Image‐Bio NED subgroup ( p < 0.05). With the subgroup of NED unreached as reference, the multivariate time‐dependent Cox model showed Image‐Only NED (HR 0.44; 95% CI 0.33–0.59) and Image‐Bio NED (HR 0.26; 0.20–0.33) were significant intermediate states that predict distinct OS for patients with intermediate‐stage HCC, which was further confirmed in the multi‐centre validation cohort. Conclusions Our study highlights the clinical course of NED states and demonstrates its dynamic prognostic significance in patients with intermediate‐stage HCC after TACE. The Image‐Bio NED is recommended to serve as an important endpoint during the dynamic management of intermediate‐stage HCC.