**1. Introduction**

Globally, hepatocellular carcinoma (HCC) is the fifth most frequent cancer, the third leading cause of cancer-related mortality, and the first leading cause of death in patients with cirrhosis. The incidence of HCC has doubled in developing and developed countries over the recent decades [3]. HCC generally takes place in the setting of variable underlying hepatic conditions,

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such as autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), hepatitis B, hepatitis C, alcohol-associated liver disease, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and other liver diseases [4]. Therefore, the patient population is varied, accounting for the intricacy of studying this neoplasm, and how to effectively manage it.

Therapeutic modalities for management of HCC can be largely categorized into three main types: surgical and nonsurgical therapies [5, 6]. Surgical therapies include surgical resection, cryosurgery, and living/deceased donor liver transplantation. Nonsurgical therapies can be divided into liver-directed and systemic. Liver-directed therapies include percutaneous ethanol/acetic acid injection, percutaneous microwave coagulation therapy, radiofrequency ablation, microwave coagulation therapy, interstitial laser photo-coagulation, targeted cryoablation therapy, high-intensity focused ultrasound, transcatheter arterial therapy, and radiation therapy. Systemic therapy includes hormonal therapy, cytotoxic chemotherapy, and novel molecularly targeted therapy.

At the time of clinical diagnosis, roughly 60%-70% of HCC patients present with primary advanced, inoperable, recurrent, or metastatic disease [7]. Moreover, tumor relapse (recur‐ rence) following curative surgical management continues to be a substantial dilemma and is documented as high as approximately 70% at 5 years postoperatively [8]. The standard of care management for recurrent HCC remains undefined [8].

The management of primary locally advanced, inoperable, recurrent, or metastatic HCC is very challenging and continues to be a topic of controversy. Herein, we shed light on the past, present, and future perspectives on the systemic therapy (hormonal therapy, cytotoxic chemotherapy, and novel molecularly targeted therapy) for the management of patients with advanced HCC.
