Therapeutic Time Migration in Hepatocellular Carcinoma: Rethinking the Timing of Systemic Therapy Across the Disease...

The management of hepatocellular carcinoma has traditionally followed a stage-dependent sequence in which surgery or thermal ablation is prioritized for early disease, transarterial approaches are used for intermediate-stage tumors, and systemic treatment is introduced after progression to advanced disease or loss of suitability for locoregional therapy. This paradigm was developed when systemic treatments had limited antitumor activity. Modern immune checkpoint inhibitors and immune-antiangiogenic combinations have substantially changed these premises. Randomized trials now demonstrate clinical benefit when systemic treatment is integrated with transarterial chemoembolization before conventional locoregional failure, while perioperative studies suggest that systemic treatment can also be moved into selected high-risk resectable disease. Conversely, updated adjuvant data indicate that simply administering systemic therapy at an earlier stage does not necessarily improve outcome after complete tumor eradication. We propose the concept of therapeutic time migration, whereby systemic treatment is introduced at an earlier biological point in selected patients, while hepatic reserve is preserved, occult systemic risk is becoming clinically relevant, and effective local treatment remains feasible. We explicitly distinguish this framework from the established concept of treatment stage migration and therapeutic hierarchy. This framework emphasizes treatment sequence rather than treatment escalation and suggests that timing itself may function as a dynamic therapeutic biomarker. Prospective studies should determine whether changing the order of systemic and locoregional therapy can modify immune activation, preserve liver function, increase conversion to definitive local treatment, and ultimately improve survival.