Several molecular-targeted agents have been tested as first- or second-line therapies for hepatocellular carcinoma (HCC) but failed to improve clinical outcomes; sorafenib has been the only approved systemic agent for treating HCC for almost 10 years. Regorafenib resulted in a significant improvement in overall survival and thus was approved for HCC patients previously treated with sorafenib. Subsequently, cabozantinib and ramucirumab demonstrated superior overall survival compared with placebos in phase III clinical trials. Immune checkpoint inhibitors such as nivolumab with or without ipilimumab and pembrolizumab are also available in some countries for patients who are unresponsive to sorafenib. Some second-line agents are available for patients who are unresponsive to sorafenib; however, little is known about the considerations for selecting appropriate secondline systemic agents. Hence, this study aimed to review the current and future perspectives of second-line systemic agents.
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Systemic therapy for hepatocellular carcinoma (HCC) has markedly changed since 2007, with
the approval of sorafenib. Sorafenib improved the overall survival of patients with advanced
HCC; however, the modest efficacy and toxicity of this therapy present unmet needs.
Subsequently, a variety of molecular targeted agents have been tested as first-line or secondline
therapies but have failed, and sorafenib has remained the only approved systemic agent
for almost 10 years. Recently, regorafenib significantly improved overall survival and was
approved for patients with HCC who have been previously treated with sorafenib. Nivolumab,
a programmed death protein-1 inhibitor, was also approved as second-line therapy, based on
remarkable response rates.
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Analysis of Existing Guidelines and Randomized, Controlled, Clinical Trials for Development of [Guideline of Clinical Trial on Herbal Medicinal Product for Liver Cancer] Ga-jin Han, Dong-hun Kim, Eun-joo Park, Sin Seong, Sung-su Kim, Jung-tae Leem The Journal of Internal Korean Medicine.2019; 40(1): 89. CrossRef
Liver cancer is the 2nd most common cause of cancer related death in Korea. Especially,
patients who present extrahepatic spread of hepatocellular carcinoma (HCC) have a shorter life
expectancy (50% survival at 1 year and less than 4 months of median overall survival). Molecular
target agent like sorafenib was usually mentioned as a treatment for them, but that was still not
firmly established. We present a 75 year-old who had expanding nodular type of HCC. The mass
was removed by resection and radiofrequency ablation. However, lung metastasis were revealed
shortly after surgery. That lesions were treated with lenvatinib and systemic chemotherapy.
There has been no proven effective therapy in the setting of advanced HCC (hepatocellular carcinoma) according to BCLC
(Barcelona Clinic Liver Cancer). Targeted therapy opened a new era in this subset of patients. Although sorafenib showed
survival benefit, objective tumor response is uncommon, while systemic chemotherapies sometimes show partial tumor
response without statistically significant survival benefits. These findings suggest evaluation of treatment response should not
depend on conventional treatment response evaluation criteria. Overall survival is now considered to be the most important
endpoint and time to disease progression can be secondary endpoint. Time to recurrence is the primary endpoint after the
curative therapy. Currently, targeted therapy in addition to known curative or palliative therapy is now under investigation
for synergistic effects, and new therapeutic agents are under development. Such advancement in the treatment of HCC will
certainly have a great impact on patients’ survival in the near future.
Most patients with hepatocellular carcinoma (HCC) present with advanced stage tumors at the time of initial
diagnosis, only about 30%, who present with early stage tumors, undergo radical therapies such as resection, liver
transplantation, and percutaneous ablation. Thus, over 50% of HCC patients receive palliative treatments. The
newly developed, molecularly targeted agents, sorafenib is the first agent that has shown significant survival
benefits for European and American patients with advanced HCC and sets the new standard for the first-line
treatment of these patients. The role of sorafenib and other promising agents should be examined in the adjuvant
setting after RFA, TACE, surgical resection or selective settings in liver transplantation in an attempt to improve
further the outcomes of these patients.