Fig. 3 |. Recommended trial designs by hepatocellular carcinoma stage.
In early-stage hepatocellular carcinoma (HCC), trials target patients with an intermediate or high risk of recurrence after curative-intent treatment, using event-free survival (EFS) (perioperative and neoadjuvant settings) and recurrence-free survival (RFS) (adjuvant setting) as primary end points, with surveillance as the control arm. Downstaging studies include patients within or beyond UNOS criteria and integrate locoregional and/or systemic therapies as the control arm according to the target population, with long-term overall survival (OS) and 2-year RFS as key end points. In intermediate-stage HCC, trials focus on patients with liver-only disease and preserved liver function who are not candidates for curative therapies, prioritizing OS and progression-free survival (PFS), with stratification by tumour burden and liver function, and transarterial chemoembolization (TACE)-based strategies as the standard comparator. In advanced-stage disease, trials include patients with Barcelona Clinic Liver Cancer (BCLC) stage B (BCLC-B) not amenable or progressing to locoregional therapy (LRT) or BCLC-C, with OS as the primary end point and systemic therapy as the control arm. Across all stages, appropriate stratification by tumour burden, liver function and key prognostic variables is essential to ensuring balance and interpretability. AFP, α-fetoprotein; ALBI, albumin–bilirubin grade; CP, Child–Pugh class; CTLA4, cytotoxic T lymphocyte-associated protein 4; ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention-to-treat; LT, liver transplantation; mVI, microvascular invasion; TARE, transarterial radioembolization; UNOS, United Network for Organ Sharing; UNOS-DS, UNOS Down-Staging; Vp, portal vein.