Hepatocellular carcinoma is now the second leading cause of death among patients with malignant tumors in China, and China accounts for more than 50% of the global incidence and deaths of hepatocellular carcinoma, 78% of which are associated with hepatitis B-based liver disease [1]. Surgery is still the first choice of treatment for hepatocellular carcinoma, but because hepatocellular carcinoma has an insidious onset and most patients (about 80%) are already in the middle or late stage of the disease when diagnosed [2], coupled with the fact that patients are often combined with cirrhosis and other factors, the surgical resection rate is low and the tumor is prone to recurrence and metastasis, so other effective treatments are urgently needed in clinical practice. Molecular targeted therapy refers to a therapeutic approach that targets certain signature molecules overexpressed by tumor cells and selects targeted blocking agents to achieve the effect of inhibiting tumor growth and metastasis. In recent years, small molecule epidermal growth factor receptor inhibitors, monoclonal antibodies against certain specific tumor cell markers, anti-tumor angiogenesis drugs and multi-target kinase inhibitors have been reported for the treatment of hepatocellular carcinoma, among which the multi-target kinase inhibitor sorafenib has been clinically proven to have clear efficacy and is widely used. 1. Efficacy in the treatment of hepatocellular carcinoma Sorafenib is a multi-targeted molecularly targeted drug that acts on the Raf-MEK-ERK signaling pathway, as well as on the tyrosine kinases of vascular endothelial growth factor receptor-2, VEGFR-3 and platelet-derived growth factor receptor-β. Sorafenib has shown potent anti-hepatocellular carcinoma activity in both cytology and animal models. A multinational, multicenter, prospective phase III randomized, controlled clinical trial (“SHARP” study) evaluated the therapeutic efficacy of sorafenib in hepatocellular carcinoma [7]. A total of 602 patients with progressive hepatocellular carcinoma who had not received any previous treatment were included in the study, including 299 patients in the treatment group who were treated with sorafenib 2 times/d at 400 mg/d, and 303 patients in the control group who were treated with placebo. The results showed that patients in the treatment and control groups had a median survival of 10.7 and 7.9 months, respectively (HR = 0.69,P = 0.001), and a median time to disease progression of 5.5 and 2.8 months, respectively (P = 0.001). Another study (“ORIENTAL” study) looked at the efficacy of sorafenib in patients with advanced hepatocellular carcinoma in the Asia-Pacific region, most of whom had a background of cirrhosis [8]. Patients were randomized in a 2:1 ratio, with 150 patients in the treatment group treated with sorafenib 2 times/d at 400 mg/d, and 76 patients in the control group treated with placebo. The median survival of patients in the treatment and control groups was 6.5 and 4.2 months (HR = 0.68, P = 0.014), respectively, and the median time to disease progression was 2.8 and 1.4 months (P = 0.001), respectively. Based on these data, the European Commission approved sorafenib for the treatment of hepatocellular carcinoma; the U.S. FDA approved sorafenib for the treatment of hepatocellular carcinoma that cannot be surgically resected; and the Chinese Food and Drug Administration approved sorafenib for the treatment of hepatocellular carcinoma that cannot be surgically resected or that has metastasized distantly. Sorafenib is the first molecularly targeted drug approved for the treatment of hepatocellular carcinoma. The high rate of recurrence and metastasis after surgery is an important factor in not obtaining a significant improvement in the survival rate of patients with hepatocellular carcinoma. For this reason, studies have been conducted to observe the efficacy of sorafenib for postoperative adjuvant therapy in patients with hepatocellular carcinoma. Animal studies have shown that intrahepatic recurrence foci can be seen 4 d after surgical resection in hepatocellular carcinoma model mice, and all mice showed recurrence foci at 2 weeks; however, treatment with sorafenib reduced the intrahepatic recurrence rate by 40% and significantly reduced the rate of intraperitoneal metastasis in mice after 2 weeks [9]. A retrospective study found that in sorafenib used as adjuvant therapy after liver transplantation in eight patients with hepatocellular carcinoma, one case (12.5%) developed tumor recurrence at follow-up, compared with four of eight control patients (50.0%); the 1-year disease-free survival rates in the two groups were 85.7% and 57.1%, respectively, and the 1-year overall survival rates were 87.5% and 62.5%, respectively [ 10]. However, a large, prospective, clinically randomized, controlled study (“STORM” study) that included 1114 patients with hepatocellular carcinoma after radical resection showed no significant differences in disease-free survival, overall survival, and time to recurrence between the sorafenib and control groups [11]. In this regard, some scholars have proposed that patients with hepatocellular carcinoma treated with radical surgery could be stratified to further observe the therapeutic efficacy of sorafenib for patients in different strata [12]. The effectiveness of combining other therapies in the treatment of hepatocellular carcinoma The effectiveness of sorafenib in the treatment of hepatocellular carcinoma has been clinically confirmed, but its overall efficacy is not satisfactory, so the effectiveness of sorafenib combined with other therapies in the treatment of hepatocellular carcinoma needs to be further investigated. 2.1 Combination with transcatheterarterial chemoembolization (TACE) is considered the standard of care for intermediate-stage hepatocellular carcinoma [13], but the long-term efficacy of TACE alone is limited. A prospective clinical study (“START” study) is evaluating the efficacy and safety of sorafenib in combination with TACE in patients with hepatocellular carcinoma. The results of an interim analysis showed that sorafenib combined with TACE had an overall disease control rate of 91.2% and an overall efficacy rate of 52.4% in 147 patients, and no serious side effects were observed [14]. A large, multicenter, retrospective study conducted in China looked at the efficacy of sorafenib in combination with TACE in 222 patients with intermediate and advanced hepatocellular carcinoma and showed a median survival of 12 months for all patients [15]. The study also performed a stratified analysis of patients with BarcelonaClinicLiverCancer (BCLC) stage C. The results showed median survival of 17 and 7.7 months for stage C1 and C2 patients, respectively, indicating that sorafenib combined with TACE therapy significantly prolonged survival in patients with preferentially selected intermediate and advanced hepatocellular carcinoma. Another cohort study including 90 patients with progressive hepatocellular carcinoma also showed that the median survival of patients in the sorafenib combined with TACE treatment group was 27 months, compared with 17 months in the TACE treatment alone group [16]. Currently, in addition to the START study mentioned above, a prospective randomized, controlled clinical study (“SPACE” study) is also evaluating the efficacy of sorafenib in combination with TACE for the treatment of intermediate stage hepatocellular carcinoma, and the preliminary results are also more The preliminary results are also satisfactory, suggesting that the research progress of sorafenib in combination with TACE for hepatocellular carcinoma should be continuously followed. 2.2 Sorafenib in combination with chemotherapeutic agents In a multicenter phase II clinical double-blind study, 96 patients with advanced hepatocellular carcinoma were randomized and treated with adriamycin (60 mg/m2) in combination with sorafenib (2 times/d, 400 mg/d) and adriamycin (60 mg/m2) in combination with placebo, respectively. After nearly 2 years of follow-up, the median survival was found to be 13.7 and 6.5 months for patients in the sorafenib and control groups, respectively (HR = 0.49,P = 0.006) [17]. A clinical study that included 53 patients with advanced hepatocellular carcinoma showed a median disease-free time of 3.7 months and a median survival of 7.4 months in patients with advanced hepatocellular carcinoma treated with sorafenib in combination with low-dose fluorouracil [18]. In another clinical study, 49 patients with advanced hepatocellular carcinoma treated with gemcitabine, oxaliplatin, and sorafenib for six courses followed by maintenance therapy with sorafenib showed a median time to disease progression of 10.3 months and a median survival of 15.7 months [19]. The role of sorafenib in combination with chemotherapeutic agents in the treatment of hepatocellular carcinoma needs to be confirmed by more prospective clinical studies. Although a phase III randomized, placebo-controlled, double-blind, parallel clinical trial of sorafenib in combination with erlotinib (“SEARCH” study) failed because it did not meet the trial endpoints, there are still ongoing trials of sorafenib in combination with other molecularly targeted drugs on Clinicaltrial.gov. The ongoing registrations are for sorafenib in combination with mapatumumab (“NCT00712855” study), sorafenib in combination with bevacizumab (“NCT00881751” study) and sorafenib The results of several prospective randomized, controlled clinical trials of sorafenib in combination with Gc33 (“NCT00976170” study) in patients with hepatocellular carcinoma are promising [20]. The main toxic side effects of sorafenib include hand-foot syndrome, diarrhea and fatigue, and the incidence of grade 3 toxic side effects can be as high as 66.7% [20], while severe toxic side effects can seriously affect the treatment and its efficacy of patients. Hand-foot syndrome is a rash and pain that occurs on the palms of the hands and feet [21]. After the onset of hand-foot syndrome, measures such as wearing protective footwear and gloves and removing keratinized skin tissue can be taken, or topical preparations containing moisturizers, corticosteroids, or urea (e.g., betamethasone ointment) can be used prophylactically before its onset. A prospective clinical randomized, controlled study that included 871 patients with hepatocellular carcinoma treated with sorafenib showed that the incidence of hand-foot syndrome was 56.0% in patients using urea cream 3 times/d (439 patients), with a median time to onset of 84 d, while the incidence of hand-foot syndrome was 73.6% in control patients (432 patients), with a median time to onset of 34 d. Data from the two groups There was a significant difference between the two groups [22]. If patients have hand-foot syndrome of degree 2 or higher, sorafenib dose reduction or temporary discontinuation is generally recommended to avoid continued progression [20,23]. Diarrhea is also a common toxic side effect of sorafenib and can be treated with antidiarrheal drugs such as loperamide. If diarrhea persists, switching to codeine phosphate may be effective. Treatment with kanamycin may be effective in some patients with diarrhea resistant to codeine phosphate therapy. However, it must be noted that excessive use of a particular antidiarrheal agent may cause constipation, thereby increasing the patient’s risk of developing hepatic encephalopathy, and should therefore be avoided. 4. Conclusion Sorafenib has a good effect in the treatment of hepatocellular carcinoma, but the current clinical use is more arbitrary and lacks specific molecular markers to guide the individualized treatment that can be applied to specific patients as in the case of malignancies such as breast cancer, metastatic colon/rectal cancer and lung cancer. In addition, the optimal combination of sorafenib with other treatments and therapeutic agents is still being explored, and there are no standardized and effective methods for the prevention and treatment of toxic side effects. Therefore, the clinical value or potential of sorafenib in the treatment of hepatocellular carcinoma remains to be further investigated.