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

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.