Systemic therapy (systemic therapy) Hepatocellular carcinoma (HCC) is difficult to treat because the same patient, the same organ, and the same time there are two very different nature of the two diseases: malignant tumors and chronic liver disease, and often interact with each other, a vicious circle. In China, HCC is common and highly prevalent, and most patients have hepatitis B and cirrhosis background, with insidious onset and rapid progression. When diagnosed, HCC often reaches the advanced stage, and more patients cannot be treated with surgery, ablation, or TACE, which results in a shorter survival period and poor prognosis; even if they can be operated on, the postoperative recurrence rate is also higher, and the long-term survival rate is low. （Therefore, it is very necessary to actively adopt various methods of comprehensive treatment, including systemic therapy.) In most cases, when liver cancer is diagnosed, patients often have different degrees of liver function abnormalities. For patients with severe hepatic insufficiency (Child-Pugh class C), only supportive symptomatic treatment is the most common and the only choice; for patients with normal or near-normal hepatic function (Child-Pugh class A or B) without indication for surgery, ablation, or hepatic arterial chemoembolization (TACE), systemic therapy can be performed. Available evidence suggests that systemic therapy is superior to supportive symptomatic therapy for patients with advanced HCC without contraindications; it can reduce tumor load, improve tumor-related symptoms and quality of life, as well as prolong survival time and other benefits. It is generally accepted that systemic therapy is mainly suitable for advanced HCC patients who have already developed extrahepatic metastases; those who have localized lesions but are not suitable for surgical resection, radiofrequency or microwave ablation, TACE, or those who have failed to progress on local therapy; those who have diffuse hepatocellular carcinoma; and those who have combined with thrombus of the main stem of the portal vein and/or the inferior vena cava. (i) Molecularly targeted drug therapy. It is known that the pathogenesis of hepatocellular carcinoma is very complex, and its occurrence, development and metastasis are closely related to mutations of multiple genes, cell signaling pathways and abnormal neovascularization, etc., in which there are several critical links, which are the theoretical basis and important potential targets for molecular targeted therapy. Molecularly targeted drug therapy has unique advantages in controlling tumor proliferation, preventing and delaying recurrence and metastasis, and improving patients’ quality of life in HCC. In recent years, the application of molecularly targeted drugs in the treatment of HCC has become a new research hotspot, and has been highly concerned and emphasized. Sorafenib is an oral multi-target, multi-kinase inhibitor, which can block tumor angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), and inhibit the proliferation of tumor cells by blocking the Raf/MEK/ERK signaling pathway, so as to exert the dual inhibition, multi-target blocking effect of anti-HCC. A number of international multicenter phase III clinical studies have demonstrated that sorafenib can delay the progression of HCC, significantly prolong the survival of patients with advanced disease, and has a better safety profile; at the same time, HCC patients with different geographic regions, different baseline levels, and different prognostic factors have shown clinical benefits from the application of sorafenib therapy, and the efficacy is similar. At present, Sorafenib has been successively approved by European EMEA, American FDA and China SFDA for the treatment of HCC that cannot be surgically resected and distant metastasis, etc. Its routine use is 400mg,po.Bid; when applying it, attention should be paid to the impact on liver function, requiring the patient’s liver function to be Child-Pugh A or relatively good grade B; liver function is good and the staging is early, The benefit is greater for those who use the drug early. Sorafenib in combination with hepatic artery intervention or systemic chemotherapy can benefit patients more, which has been confirmed by some clinical observations and studies; as for the combination with other treatments (surgery, radiofrequency ablation and radiotherapy, etc.), studies are underway. Clinical trials of other new molecular targeting drugs, single drug or combined with surgery, interventional therapy and systemic chemotherapy for liver cancer are also underway. (ii) Systemic chemotherapy (systemic chemotherapy). Systemic chemotherapy (系统化疗) refers to the way of chemotherapy which is mainly administered by oral, intramuscular or intravenous route. Systemic chemotherapy has been used in the treatment of hepatocellular carcinoma since as early as the 1950s, and it is a commonly used palliative treatment. Most traditional cytotoxic drugs, including ADM/EADM, 5-Fu, PDD and MMC, have been tried in hepatocellular carcinoma, but the single-agent efficacy rate is relatively low (generally <10%), and there is a lack of high-level evidence-based medical evidence of survival benefit; only a few individual studies have suggested that ADM-containing systemic chemotherapy may prolong the overall survival time of patients with advanced HCC, compared to BSC; meanwhile, the efficacy rate is low, and the toxicity side effects are poor. At the same time, poor reproducibility and obvious toxic side effects have seriously affected its clinical application and efficacy. Therefore, for many years, the relevant research is relatively small, low level and stagnant. 1, Arsenious acid injection. Arsenic trioxide (As2O3, arsenious acid) is the main component of the traditional Chinese medicine arsenic, and our scholars firstly applied its injection (arsenious acid injection) to treat promyelocytic leukemia, which made a significant breakthrough. 2004, the results of the domestic multi-center collaborative clinical research showed that the use of arsenious acid injection in the treatment of middle- and late-stage primary hepatocellular carcinoma has a certain palliative effect, and it can control the progression of the disease, improve the quality of life of patients, alleviate cancer pain, and improve the quality of life of the cancer patients. It can control the disease progression, improve the quality of life of patients, reduce cancer pain and prolong the survival period, and at the same time, the adverse effects are mild and well tolerated by patients; therefore, arsenite injection has been approved by SFDA to increase the indications of advanced liver cancer, and it has become the first systemic chemotherapeutic drug approved for the treatment of liver cancer through the proof of effectiveness in multi-center clinical studies. In clinical application, attention should be paid to the selection of appropriate patients and to the active prevention and treatment of adverse reactions, especially liver and kidney toxicity. 1. FOLFOX regimen. In recent years, oxaliplatin (OXA) and other new generation chemotherapeutic drugs have been introduced and applied one after another, which has led to obvious progress in chemotherapy for gastrointestinal cancer and significant improvement in prognosis, and promoted and inspired the research on chemotherapy for hepatocellular carcinoma, so that the traditional concept that hepatocellular carcinoma is not suitable for systemic chemotherapy has been challenged and questioned. A series of clinical observations and phase II studies have been conducted both at home and abroad, all of which suggest that OXA-containing regimens are effective in treating hepatocellular carcinoma, with improved objective efficiency, capable of controlling the progression of the disease, alleviating the symptoms, and prolonging the survival, and have thus been widely emphasized. 2010 International Multicenter Study of FOLFOX 4 Regimen Controlled by Single-agent ADM for Palliative Chemotherapy of Advanced Hepatocellular Carcinoma Patients Not Suitable for Surgery or Local Treatment (EACH). The results of the phase III clinical study (EACH study) have been published, and it has been proved that OXA-containing combination chemotherapy can bring better objective efficacy, disease control, and survival benefit to patients with advanced HCC, and has a good safety profile. This study has been highly valued by international and domestic academics, changing the status quo of the long-term lack of standard regimens for systemic chemotherapy in advanced HCC and causing a major change in the concept of hepatocellular carcinoma treatment. It is currently believed that HCC is a tumor with some sensitivity to new chemotherapy regimens such as OXA-containing regimens. For advanced HCC patients without contraindications, systemic chemotherapy is obviously better than general supportive therapy, and it is not a choice of treatment method, and its main indications are: (1) advanced patients combined with extrahepatic metastases; (2) localized lesions, but not suitable for surgical treatment and hepatic artery interventional embolization chemotherapy, such as diffuse hepatic lesions or hepatic vascular degeneration; (3) combined with the trunk of portal vein or the inferior vena cava (4) Patients with hepatic vascular obstruction after repeated hepatic artery chemoembolization (TACE) and recurrence after interventional therapy. Of course, systemic chemotherapy should strictly control the clinical indications, timely evaluate the efficacy, and closely monitor and prevent adverse reactions. In principle, systemic chemotherapy is not suitable for patients with one of the following conditions: ECOG>2, Child-Pugh>7; ②White blood cells<3.0×109/L or neutrophils<1.5×109/L, platelets<60×109/L, hemoglobin<90g/L; ③Abnormalities in liver and renal function, aminotransferase (AST or ALT)>5 times the normal value and/or bilirubin<90g/L. (iii) Significantly abnormal liver and renal function, aminotransferase (AST or ALT) > 5 times the normal value and/or bilirubin significantly elevated > 2 times the normal value, serum albumin < 28g/L, creatinine (Cr) ≥ the upper limit of the normal value, creatinine clearance (CCr) ≥ 50mi/min; (iv) Infected with fever, hemorrhagic tendency, medium to large amount of abdominal fluid and hepatic encephalopathy. 3.Other drugs. Since several international randomized clinical studies (RCTs) have not demonstrated a survival benefit, the application of triptans, anti-androgen drugs, or octreotide is not recommended as systemic therapy against hepatocellular carcinoma. However, octreotide can be used to control hepatocellular carcinoma combined with gastrointestinal bleeding and relieve intestinal obstruction except. (iii) Traditional Chinese medicine treatment. Traditional Chinese medicine can help reduce the toxicity of radiotherapy and chemotherapy, improve cancer-related symptoms and quality of life, and prolong the survival period, which can be an important auxiliary means for liver cancer treatment. In addition to the traditional diagnosis and treatment and the use of tonics, over the years, China's drug regulatory authorities have approved several modern Chinese medicinal preparations for the treatment of hepatocellular carcinoma, including Carbapenem, Kanglite, Huazhaxin, Elemene and Delisol injection and their oral dosage forms, etc. These preparations have been widely used in clinics and accumulated much practical experience, with certain curative effects and their own characteristics, and the patients' adherence, safety and tolerance are all better, but these preparations have been widely used in clinics and accumulated many practical experiences. However, these drugs have been on the market for many years, and the early experimental and clinical studies are relatively weak and lack of high-level evidence-based medical evidence to fully support them, so it is necessary to actively conduct in-depth research. (iv) Other treatments. It is generally believed that biological therapy can improve the quality of life of liver cancer patients, help to improve anti-tumor efficacy and reduce the recurrence rate after surgery. Appropriate application of thymopeptide α1 can enhance the immune function of the body, which has auxiliary antiviral and antitumor effects; and after resection of HCC patients with viral hepatitis B-related HCC, long-term application of α-interferon and its long-acting preparation as auxiliary treatment can effectively delay recurrence and reduce the recurrence rate. For HCC patients with a background of hepatitis B and/or C, special attention should be paid to checking and monitoring viral load (HBV DNA/HCV RNA) and hepatitis activity. It is known that the above anti-tumor drug treatments (including TAI/TACE, molecular targeted therapy and chemotherapy) have the potential to activate hepatitis viruses; and active viral replication and hepatitis activity often impair the liver function of patients and significantly affect the implementation and effectiveness of anti-tumor therapy, which should be highly valued. If hepatitis virus replication is found to be active, antiviral therapy must be carried out in a timely manner, and nucleoside analogs, α-interferon and its long-acting preparation, and thymosin α1 can be used. In addition, throughout the treatment of hepatocellular carcinoma, comprehensive consideration should be given to strengthening the supportive symptomatic treatment, including analgesia, protecting liver function, choleretic, correcting anemia, improving nutritional status, controlling blood glucose in patients with diabetes mellitus, correcting hypoproteinemia, controlling abdominal fluid accumulation, and preventing complications such as gastrointestinal hemorrhage. These supportive and symptomatic treatment measures are very important and necessary to alleviate pain, improve patients' quality of life, and ensure the smooth implementation of antitumor therapy and its effects.