Treatment of Advanced Hepatocellular Carcinoma

*Mahmoud Aryan, Ellery Altshuler, Xia Qian and Wei Zhang*

#### **Abstract**

Hepatocellular Carcinoma (HCC) is the fifth most common cancer and represents the fourth most common cause of cancer related death worldwide. Treatment of HCC is dictated based upon cancer stage, with the most universally accepted staging system being the Barcelona Clinic Liver Cancer (BCLC) staging system. This system takes into account tumor burden, active liver function, and patient performance status. BCLC stage C HCC is deemed advanced disease, which is often characterized by preserved liver function (Child-Pugh A or B) with potential portal invasion, extrahepatic spread, cancer related symptoms, or decreased performance status. Sorafenib has been the standard treatment for advanced HCC over the past decade; however, its use is limited by low response rates, decreased tolerance, and limited survival benefit. Researchers and clinicians have been investigating effective treatment modalities for HCC over the past several years with a focus on systemic regimens, locoregional therapy, and invasive approaches. In this systemic review, we discuss the management of advanced HCC as well as the ongoing research on various treatment opportunities for these patients.

**Keywords:** hepatocellular carcinoma, advanced stage, systemic therapy, locoregional therapy

#### **1. Introduction**

Primary liver cancer represents an enduring global threat as the fifth most common cancer worldwide and the second highest global cause of cancer-related mortality [1]. The most common form of liver cancer is hepatocellular carcinoma (HCC), which makes up over 90% of primary hepatic malignancies and independently represents the fourth most common cause of cancer-related death worldwide [2, 3]. Hepatotropic viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) are the most common causes of HCC, accounting for at least 80% of cases. HCC is also prevalent in individuals with underlying cirrhosis with other risk factors being alcohol use, non-alcoholic fatty liver disease (NAFLD), diabetes mellitus, obesity, aflatoxin exposure, hereditary hemochromatosis, tobacco use, oral contraceptive use, and other inherited metabolic disorders including tyrosinemia and glycogen storage disease type 1 (Von Gierke disease) [4–7].

The American Association for the Study of Liver Disease (AASLD) recommends that adults with cirrhosis undergo screening for HCC given the overall observed mortality benefit. Surveillance consists of abdominal ultrasonography every six

months either with or without alpha fetoprotein (AFP) measurement. Patients who have a lesion ≥ 1 cm or AFP measurement ≥ 20 ng/mL are recommended to undergo further diagnostic evaluation with multiphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen [8, 9]. In some instances, HCC can be diagnosed radiographically via LI-RADS criteria (LR-5 is diagnostic), which consists of imaging findings of washout, enhancing capsule, and threshold growth in addition to overall size diameter increase over the course of months [10]. In instances in which lesions are indeterminate or cannot be diagnosed radiographically, patients typically undergo either biopsy or close interval repeat imaging [8].

Solid tumor oncological staging is usually based on the tumor (T), node (N), and metastasis (M) classification system. This system does not take into account the degree of liver dysfunction or patient performance status and is less useful for predicting the course of HCC [9]. The Barcelona Clinic Liver Cancer (BCLC) staging system is the most universally accepted staging system for HCC as it takes into account tumor burden, liver functional status, and patient performance status. In the BCLC system, patients are classified into different stages, including very early (BCLC stage 0), early (BCLC stage A), intermediate (BCLC stage B), advanced (BCLC stage C), and terminal (BCLC stage D). Very early to early-stage HCC (BCLC stage 0 or A) cancers are treated with curative intent through resection, ablation, or even liver transplant (LT); overall survival is as high as 75% at 5 years. The standard of care for patients with intermediate stage HCC (BCLC stage B) is transarterial chemoembolization (TACE) or transarterial radioembolization (TARE). Patients with advanced HCC (BCLC stage C) often present with cancer-related symptoms but usually have moderately preserved liver function (Child-Pugh A or B). These patients receive systemic therapy, though other treatment modalities are under investigation. BCLC stage D HCC is considered terminal and is usually managed with best supportive care [11, 12].

Unfortunately, over 80% of HCC are diagnosed at the advanced stage (BCLC stage C or D). Therapy options such as TACE and tumor resection are often not appropriate in these patients, and 5-year survival is as low as 18% [13, 14]. Researchers and physicians have been investigating potential effective treatment options in these patients in the past decade and have made great advances. In this systemic review, we summarize the latest strategies and upcoming methods of managing advanced (BCLC stage C) HCC.

#### **2. First line systemic therapy**

HCC has been historically considered a chemotherapy-resistant tumor. Most chemotherapy agents require hepatic metabolism and cannot be used in the setting of severely impaired liver function [15]. Overall survival is often dictated by underlying hepatic function rather than extensive tumor burden. Despite these challenges, researchers have applied targeted immunotherapy for advanced HCC treatment and, at least in certain clinical scenarios, have found benefit [16].

#### **2.1 Atezolizumab + Bevacizumab combination therapy**

Multi-agent combination therapy with atezolizumab and bevacizumab has recently replaced sorafenib as first line treatment for advanced HCC. Atezolizumab and bevacizumab are monoclonal antibodies that target program death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF), respectively [17, 18]. When used together, these medications inhibit both T cell apoptosis and angiogenesis. The combination of these medications was compared to sorafenib in patients

*Treatment of Advanced Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.99837*

with treatment naïve advanced HCC in the IMbrave150 trial. The trial showed that patients treated with atezolizumab and bevacizumab had significantly improved overall survival (OS) and progression free survival (PFS) when compared to those treated with sorafenib [17]. Adverse events occurred at similar rates among the two groups, with the most common adverse effects in patients given atezolizumab with bevacizumab being hypertension and proteinuria. Following systemic review of nine randomized control trials, the American Society of Clinical Oncology (ASCO) has deemed combined atezolizumab/bevacizumab as the first line treatment for advanced HCC applicable to those with Child-Pugh A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) no higher than one and treated esophageal varices (EV) [18]. Recent updates from Finn and colleagues on the IMbrave150 trial reported that median OS was 19.2 months in those taking atezolizumab and bevacizumab vs. 13.4 months in those taking sorafenib (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009). At 18 months, those treated with atezolizumab and bevacizumab had an OS of 52% while patients on sorafenib has an OS of 40%. Atezolizumab and bevacizumab combination therapy has demonstrated the longest OS in a front-line phase III clinical study for advanced HCC to date and remains the standard of care for treatment-naïve, advanced HCC [19].

### **2.2 Sorafenib**

Tyrosine protein kinase inhibitors (TKIs) had been at the forefront of advanced HCC treatment for quite some time. The first TKI approved by the Food and Drug Administration (FDA) for treatment of advanced HCC was sorafenib, which was first approved for treatment of unresectable HCC in 2007 (**Table 1**). This TKI targets VEGF, platelet derived growth factor (PDGF), and others molecular pathways to inhibit angiogenesis [20]. The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study was the first multi-center, placebo-controlled, phase III clinical trial in untreated, Child-Pugh A advanced HCC patients, and demonstrated a 2.8-month overall survival (OS) in those treated with sorafenib versus placebo (10.7 vs. 2.9 months) [21]. Further clinical trials and subset analysis showed that sorafenib provides survival benefit in patients with HCC not amendable to loco-regional therapy, though the benefit appears to be greater for patients


#### **Table 1.**

*American Society of Clinical Oncology (ASCO) recommendations for systemic therapy in advanced (BCLC stage C) HCC [18].*

with Child Pugh A cirrhosis than Child Pugh B cirrhosis [22]. Cheng et al. performed a randomized, double-blind, placebo control trial of sorafenib in the Asian Pacific region in patients with advanced HCC. Following six weeks of therapy, patients treated with sorafenib had significantly higher median OS (6.5 months vs. 4.2 months; [HR] 0.68 [95% CI 0.50–0.93]; p=0.014) and time to progression (2.8 months vs. 1.4 months; HR 0.57 [0.42–0.79]; p=0.0005) [23]. Despite the clinical benefits of sorafenib, many patients are unable to tolerate the significant side-effects, which include diarrhea, hand and feet skin irritation, weight-loss, and electrolyte derangements [21, 24, 25]. With its OS benefits and effects on disease progression, sorafenib remains a first-line option for advanced HCC [18].

### **2.3 Lenvatinib**

Following the success of Sorafenib, several other TKIs were developed as potential treatment options in advanced HCC patients. Lenvatinib is a TKI that targets multiple pathways within angiogenesis including VEGF receptors, fibroblast growth factor (FGF) receptors, platelet derived growth factor (PDGF) alpha as well as RET and KIT [26]. An open-label, multicenter, phase III clinical trial known as the REFLECT trial showed lenvatinib to be non-inferior to sorafenib in advanced HCC patients with respect to OS. In the same trial, patients treated with lenvatinib had a higher incidence of hypertension, decreased appetite, and weight loss, while those treated with sorafenib had a higher incidence of hand-foot skin reaction (HFSR) and diarrhea. Patients treated with lenvatinib had significantly better progression-free survival (PFS) (7.4 months vs. 3.7 months, p < 0.001), time to progression (8.9 months vs. 3.7 months, p < 0.001), and objective response rate (24.1% vs. 9.2%, p < 0.001) [25, 27]. Vogel et al. analyzed prognostic factors of the REFLECT trial and reported that baseline liver function tests such as albuminbilirubin grade and Child-Pugh score were predictive of OS. These markers may be used to monitor overall safety and efficacy of lenvatinib treatment. Regardless of baseline liver function, lenvatinib led to longer OS than sorafenib [28]. Given this data, the ASCO now considers lenvatinib a reasonable first-line treatment option for advanced HCC [18].

Ongoing studies are being conducted on the use of lenvatinib alongside nivolumab, an anti-PD-1 monoclonal antibody often used as second line therapy for HCC, in patients with unresectable, advanced HCC. Early results from the phase 1b trial of this open label study show that lenvatinib combined with nivolumab is well tolerated in BCLC stage C HCC with multiple patients demonstrating partial or complete response [29].

### **3. Second line systemic therapy**

#### **3.1 Cabozantinib**

Other agents have been investigated for advanced HCC for patients with disease resistant to first-line therapy. Cabozantinib is a TKI that targets mesenchymalepithelial transition (MET) factor to disrupt hepatocyte growth factor pathway, a pathway that is often important for HCC oncogenesis [30]. A phase III clinical study known as the CELESTIAL trial showed that for patients who had suffered disease progression while on sorafenib, cabozantinib led to longer OS and PFS than placebo [31–33]. Although adverse effects such as diarrhea, HFSR, hypertension, nausea, and decreased appetite, were found to be twice as high in the cabozantinib group

than in the placebo group, the effects were generally mild and considered manageable [31–33]. Given its clinical benefit, the ASCO has classified cabozantinib as a second-line therapy for advanced HCC [18].
