Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST

Recent advancements have improved the management of patients with liver cancer. Results of studies have informed how to stage and decide the optimal treatment option for-each patient with an adequate balance between risks and benefits. The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy has been widely endorsed for this purpose. This is not a rigid system: One of the key aspects in the management of patients is the optimal timing for systemic treatment initiation and for declaring tumor progression and/or treatment failure. Some patients at intermediate or even early stage may be considered for systemic therapy as options of higher priority may have failed or may not be feasible. Sorafenib is the sole systemic agent that has shown efficacy in phase 3 trials. Other agents (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety and/or survival benefit. Optimal sorafenib administration and adequate adherence of the patients are crucial requirements to obtain the benefits of the drug. Because development of adverse events has been shown to correlate with better outcome, careful dose adjustments should be in place while avoiding unnecessary treatment interruption. Furthermore, recent studies have shown that progression at imaging may not translate in poor prognosis and that treatment beyond progression may be considered if there is no option for a second-line research trial. In this review, the authors examine all of the controversial aspects that affect treatment initiation and maintenance, how response to treatment should be evaluated, and define the needs that are faced by current research.