Hepatocellular carcinoma (HCC) is a poor prognosis tumor when not accessible to potentially curative treatments such as surgical resection, thermal ablations or liver transplantation. Systemic cytotoxic chemotherapies have shown inconsistent clinical benefit. In 2007, sorafenib, a tyrosine kinase inhibitor (TKI), was the first systemic therapy able to significantly improve the outcome of HCC patients non-eligible for curative or loco-regional therapies, despite a modest tolerance and low tumor objective response rate (ORR). Among the newer TKIs approved after 2017, lenvatinib was the first to show a striking ORR and demonstrate non-inferiority vs. sorafenib in the first-line setting. Furthermore, phase 3 trials showed the benefit of other TKIs, regorafenib and cabozantinib, and the anti-angiogenic ramucirumab monoclonal antibody, in systemic second-line therapy. Immune checkpoint inhibitors targeting PD1, achieved striking tumor shrinkage in some patients in monotherapy, seeming to be associated with exciting outcomes. Unfortunately, this occurred in too few patients to improve the median overall survival. More recently, the combination of anti-angiogenic drugs targeting the liver microenvironment with PD-1/PD-L1 inhibitors, such as the combination of bevacizumab and atezolizumab, proved to be substantially effective in phase 3, and other combinations of PD-1/PD-L1 and CTLA-4 inhibitors or TKIs have raised a lot of hopes for the systemic treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis, which is mainly caused by tumor recurrence and metastasis. Circulating tumor cells (CTCs) are tumor cells shed into the bloodstream and regarded as the “seeds” of tumor recurrent or metastatic lesions. Over the past decade, the clinical value of CTC analysis has been extensively explored. CTC analysis is a representative form of liquid biopsy, offering a novel solution that can bypass the problems of invasive biopsy procedures, enabling comprehensive, non-invasive, and real-time disease monitoring. In HCC, CTC analysis has facilitated early detection and prognosis prediction, as well as treatment monitoring and therapeutic intervention guiding. In this review, we summarize available literature and provide an overview of CTC biology, detection technologies, and clinical applications in the diagnosis, prognosis prediction, and personalized treatment of HCC.