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

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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 ( R 2 = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation ( R 2 = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS ( R 2 = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation ( R 2 = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS ( R 2 = 0.856, R = 0.925, p = 0.003) as did PFS ( R 2 = 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.