Review article: systemic treatment of hepatocellular carcinoma

Abstract

SummaryBackgroundThe approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first‐ and second‐line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.AimTo summarise the evolving field of systemic therapy of hepatocellular carcinoma.MethodsWe reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.ResultsWe discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.ConclusionsThe tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib‐experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib‐experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

Programmed cell death protein‐1 (PD‐1)‐targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real‐world cohort

“…Despite recommendations for surveillance of patients at risk, HCC is often diagnosed at an advanced stage where only systemic treatment can be offered. Many patients develop recurrence or disease progression after initial surgical or loco‐regional treatment and then become candidates for palliative systemic therapy . For the last decade, the tyrosine kinase inhibitor sorafenib was the only effective drug available for HCC, with two randomised controlled phase III trials showing a survival benefit compared to placebo .…”

“…Many patients develop recurrence or disease progression after initial surgical or loco‐regional treatment and then become candidates for palliative systemic therapy . For the last decade, the tyrosine kinase inhibitor sorafenib was the only effective drug available for HCC, with two randomised controlled phase III trials showing a survival benefit compared to placebo . Only recently, three more tyrosine kinase inhibitors were approved for HCC, lenvatinib in first‐line and regorafenib and cabozantinib in second‐line drug treatment .…”

“…HCC may also be an attractive candidate for immunotherapy, as it represents an immunogenic tumour, but also fosters an immunosuppressive microenvironment (eg, by up‐regulation of immune checkpoint molecules). This may be further supported by the tolerogenic liver milieu and chronic inflammation due to the underlying liver disease . Notably, overexpression of the checkpoint molecules programmed cell death‐ligand 1 (PD‐L1) and programmed cell death protein‐1 (PD‐1) was associated with tumour aggressiveness and postoperative recurrence in HCC …”

Systematic review with meta‐analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib

“…Thus, if all these agents are approved for the systemic treatment of hepatocellular carcinoma, physicians will have to carefully evaluate the benefits of one drug over the other . In the first‐line treatment the decision to opt for sorafenib or lenvatinib will depend on the easiness of administration, the magnitude of adverse events and the economic impact …”

Proteomic analysis of the molecular mechanism of curcumin/β‐cyclodextrin polymer inclusion complex inhibiting HepG2 cells growth

“…Hepatocellular carcinoma (HCC) remains the second deadliest cancer all over the word (Pinter & Peck‐Radosavljevic, ). It was estimated that more than one million new HCC patients are diagnosed every year (Wang et al, ).…”