Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era

SIMPLE SUMMARY: Systemic chemotherapies have revolutionized therapeutic paradigms for hepatocellular carcinoma (HCC) over the past decade. Various regimens have progressively become standard-of-care in clinical practice. However, there are no reports regarding the impact of multiple sequential therapies including immune-oncologic agents on their outcomes. This study investigated the change, over three time periods, in survival for patients with unresectable HCC, and the effects of sequential treatments on their outcomes. The results showed that the number of patients who received more than two lines steadily increased, and the overall survival significantly improved over time. Surprisingly, the 3-year survival rate increased from 12.1% in the early period to 44.4% for the most recent period. Using less than three lines, the non-objective response of the first line and extrahepatic metastasis were identified as the strongest drivers of a worse prognosis. Sequential treatment post-progression is valuable for prolonging survival. ABSTRACT: Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.