First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

Abstract

Advanced hepatocellular carcinoma (HCC) with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC) classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI) sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) is helpful to identify patients who do not benefit from sorafenib treatment.

Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma

“…There are several treatment strategies available for HCC, including surgical resection, transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection and liver transplantation [ 97 ]. More recently, the identification of mechanisms that play a crucial role in HCC pathogenesis, such as neoangiogenesis, has led to development of systemic targeted therapies [ 98 ]. However, currently sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only systemic agent found to increase survival time in patients with locally advanced and/or metastatic HCC who are not candidates for either resection or liver transplantation and have failed to respond to locoregional therapies [ 99 ].…”

Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study

“…All of patients in TACE+C+L group completed the follow-up with good compliance. Compared to sorafenib treatment, the dermatological reactions, fatigue, diarrhea, and arterial hypertension associated with sorafenib usually compel dose reduction or interruption of treatment [ 41 ].…”

Sequential Systemic Treatment in Advanced Hepatocellular Carcinoma Is Able to Prolong Median Survival to More than 3 Years in a Selected Real-World Cohort

“…Since the SHARP trial in 2008, sorafenib (SOR) has served as a standard first-line systemic treatment for advanced HCC [6, 7]. After several years of disappointing failures in phase III clinical trials [3, 8], lenvatinib (LEN), an anti-angiogenic tyrosine kinase inhibitor (TKI), has been demonstrated to be non-inferior to SOR as a first-line treatment (overall survival [OS] 13.6 vs. 12.3 months, hazard ratio 0.92, 95% CI 0.79–1.06), and has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA) [9]. Regarding second-line therapy, regorafenib (REG), another multikinase inhibitor, was the first agent tested positive in a phase III clinical trial with benefit in terms of OS af­ter tumor progression on SOR compared to placebo (RESORCE trial; OS 10.6 vs. 7.8 months, hazard ratio 0.63, 95% CI 0.50–0.79) [10].…”