Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma

Aim: Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. Methods: Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. Results: In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R² = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation (R² = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R² = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation (R² = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R² = 0.856, R = 0.925, p = 0.003) as did PFS (R² = 0.946, R = 0.973, p < 0.001). Conclusions: PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.