**Abstract**

Systemic therapy of advanced stage hepatocellular carcinoma (HCC) was limited to the sorafenib in the past decade since 2007. Novel agents including multiple targeting agents, immune checkpoint inhibitors and anti-angiogenesis reported efficacy in treatment. This is the first time, the combination of atezolizumab and bevacizumab as first-line treatment is superior to sorafenib. Standard guideline in advanced HCC was changing. New novel drugs increase in available including multiple targeting agents and immune checkpoint blockade such as Lenvatinib, regorafenib, cabozantinib, ramucirumab and immunotherapy as first line or second line therapy will benefit in term of survival benefit and quality of life in advanced stage or unresectable hepatocellular carcinoma.

**Keywords:** hepatocellular carcinoma, immunotherapy, targeted therapy, systemic therapy, advanced stage

#### **1. Introduction**

During the many years, numerous randomized control clinical studies have been performed for testing treatments for advanced hepatocellular carcinoma (HCC) [1]. Historical studies performed to prove efficacy of cancer chemotherapy as single agent or in combination. However, this class of cancer therapy have had no proven benefits on overall survival in advanced stage HCC. Sorafenib a multi-tyrosine kinase inhibitor with antiangiogenesic effects showed a survival benefit and it was established as first-line systemic therapy for advanced stage HCC patients or progression form locoregional therapy since 2007. In recent years, there are new agents has been approved for advanced stage HCC as first line and second line options. Exploratory analyses of these drugs indicate that a cumulative median overall survival more than 20 months with good liver function and quality of life.

#### **2. Systemic chemotherapy**

Historically, systemic chemotherapy has not shown survival efficacy in treatment of HCC when used in advance stage HCC. This result comes from single-arm, open label studies evaluating the use of some traditionally chemotherapeutic, that did not lead in the past years and limiting their use in palliative setting or some situations. Single agent anthracyclines and fluoropyrimidines have been most widely used in clinical practice in the past. Unfortunately, that result reported poor response rates and short timing in tumor progression [2]. New chemotherapeutic

agents, such as oxaliplatin, have shown clinical benefit in cancers of gastrointestinal tract (stomach cancer, colorectal cancer, or pancreatic cancer). These drugs have also been evaluated for the treatment of advanced stage setting with some benefit findings. As previously said, rational of combination use of chemotherapy might be a valuable option for advance stage HCC. FOLFOX4 regimen (Fluorouracil, leucovorin, oxaliplatin) was evaluated efficacy in comparison with single agent of doxorubicin for advanced stage HCC patients whom ineligible for locoregional therapies or surgery in Phase III EACH study [3]. FOLFOX4 had better results in term of progression free survival (PFS) (2.93 mons vs. 1.77 mons, *P* < 0.001) and in response rate and disease control rate. Although, these positive results and good safety profile in adverse effect but do not necessarily translate to better overall survival that is primary endpoint of the study (6.40 mons vs. 4.97 mons, *P* = 0.07), leading to a negatively result of study. Still, an unplanned subsequent analysis performed at 7 months after the end of the previous study has shown an improvement of survival outcomes (6.46 mons vs. 4.90 mons, *P* = 0.04) but progression free survival, response rate and disease rate control in the Chinese populations [4], leading to FOLFOX4 approval in Chines FDA for advanced HCC. Others, combination drug, GEMOX regimen (Gemcitabine, oxaliplatin) was evaluated in a large, multicenter retrospective study (AGEO) [5]. Results of the study had high response rate with 22%, 66% disease control rate and 4.5 months with 11.0 months in term of progression free survival and overall survival. This interesting result should be considered, response to GEMOX led to better overall survival in comparison with lack of response but possible serious side effects of this regimen (Neurotoxicity, thrombocytopenia, neutropenia, and diarrhea). Furthermore, studies are therefore required in phase III trial to assess the role of this regimen in treatment of advanced stage HCC. Some other oxaliplatin-based regimens have been studies in phase II studies, showing interesting results, such as XELOX (oxaliplatin plus capecitabine) or GP (Gemcitabine plus cisplatin) [6, 7]. Meta-analysis study defined the efficacy of oxaliplatin-based regimens but it as an important limitation having evaluated only small single arm studies [8].

All this result suggests that better efficacy in some situation could be obtained with oxaliplatin-base regimen and GEMOX combination in some setting. But current trials are emerging and focusing on targeted therapies and immunotherapy that have significantly improve survival outcome.
