As a systemic disease, hepatocellular carcinoma can be treated by various local treatments in the early stage, including surgical resection, hepatic artery chemoembolization, radiofrequency ablation, anhydrous alcohol injection, etc. However, due to the insidious onset, most patients with hepatocellular carcinoma have advanced hepatocellular carcinoma and lose the opportunity of radical treatment such as surgical resection and local ablation. For patients with unresectable progressive and metastatic hepatocellular carcinoma, systemic therapy is currently the main treatment strategy, which mainly includes molecular targeted therapy, chemotherapy and immunotherapy. The latest international guidelines and the newly promulgated 2019 “Diagnostic and Treatment Standard for Primary Liver Cancer” by the Health Care Commission have made molecular targeted therapy as the standard treatment strategy for advanced liver cancer. However, there are many choices of molecular targeted therapy drugs for liver cancer, and how to make a reasonable choice to improve the therapeutic efficacy is the main concern of patients.
First of all, we need to clarify which liver cancer patients need molecular targeted therapy.
According to the international authoritative guidelines and the treatment standard of the Ministry of Health, molecular targeted therapy is recommended for the following types of liver cancer patients.
1, patients with intrahepatic large vessel invasion (such as portal vein, hepatic vein, inferior vena cava) at the time of diagnosis of hepatocellular carcinoma
2. patients with liver cancer combined with distant metastases, such as lymph node metastases, lung metastases, bone metastases, and brain metastases
3. patients with multiple tumors in the liver and poor results of interventional therapy, although there is no vascular invasion or distant metastasis.
Which patients are not suitable for molecular targeted therapy?
Although molecular targeted therapy for hepatocellular carcinoma is recommended by domestic and international guidelines as the main treatment strategy for progressive or metastatic hepatocellular carcinoma, the following patients are not suitable for molecular targeted therapy.
1. Patients with severe liver function loss, including jaundice, hepatic encephalopathy, refractory ascites or hepatorenal syndrome.
2, patients with hepatocellular carcinoma with poor strength score (ECOG ≥ 2).
3, patients with hepatocellular carcinoma with severe co-infection.
4, patients with active bleeding (such as gastrointestinal bleeding) liver cancer.
5, patients with liver cancer with severe cardiac, pulmonary and renal insufficiency.
6. patients who are pregnant or breastfeeding.
What are the current molecular targeted therapeutic drugs for liver cancer?
First-line molecular targeted therapy drugs.
First-line molecular targeted therapy is the first recommended by the guidelines and the most therapeutically efficient molecular targeted drugs, including
1.Sorafenib
Sorafenib is the first first-line targeted therapy drug approved by FDA for advanced hepatocellular carcinoma. As an oral tyrosine kinase inhibitor, sorafenib inhibits tumor proliferation and neovascularization by blocking the RAF/MEK/ERK signaling pathway and inhibiting VEGF, PDGFR. The SHARP clinical study in Europe and the United States and the ORIENTAL international multicenter clinical study in Asia Pacific have confirmed the efficacy and safety of sorafenib in advanced hepatocellular carcinoma, ushering in an era of targeted therapy for hepatocellular carcinoma. These two prestigious international multicenter clinical studies demonstrated the survival benefit of sorafenib in patients with hepatocellular carcinoma of different races and geographic regions.
2. Lenvatinib
After sorafenib was approved as the first-line drug for advanced hepatocellular carcinoma in 2007, a number of anti-vascular molecular targeted drugs have been launched in large international phase III clinical trials, such as brinib (Brivanib), sunitinib (Sunitinib), linifanib (Linifanib), etc. However, all these drugs failed to surpass sorafenib in terms of efficacy in controlling hepatocellular carcinoma, and the trials all However, these drugs failed to outperform sorafenib in controlling liver cancer, and the trials ended in failure. Lenvatinib (E7080) is a novel tyrosine kinase inhibitor, and in 2018, an open, multicenter, phase III non-inferiority study (REFLECT) demonstrated that lenvatinib was non-inferior to sorafenib in terms of overall survival OS. Of particular note, a subgroup analysis of the REFLECT study found a significant survival benefit of lenvatinib in Asian patients with hepatocellular carcinoma, particularly those with hepatitis B-related hepatocellular carcinoma. Based on the REFLCET study, lenvatinib has received marketing approval from the FDA in Japan, Europe and the United States, and China, and has been included as a Class I recommendation in the 2018 edition of the CSCO Guidelines for the Treatment of Primary Liver Cancer.
Second-line molecular targeted therapeutic agents.
Second-line molecular targeted drugs are drugs chosen when first-line targeted therapies fail or are resistant, or when first-line drugs cannot be tolerated. Currently, the second-line targeted drugs for advanced liver cancer include
1.Regafenib
For a long time, it has been very difficult to explore second-line targeted therapy after sorafenib treatment failure, and many international large phase III clinical studies have ended in failure, including anti-angiogenic small molecule targeted drug brinib, mTOR inhibitor everolimus, etc. Regorafenib is a fluorogenic drug of sorafenib, whose molecular structure is similar to sorafenib and can inhibit multiple kinases in the tumor microenvironment, with anti-angiogenic and anti-tumor cell proliferation effects.In 2016, the RESORCE clinical study of regorafenib for second-line treatment of advanced hepatocellular carcinoma found that regorafenib prolonged patients’ median survival and median disease-free survival compared with placebo. Based on the RESORCE study, in 2017, the U.S. FDA and Chinese FDA approved regorafenib for sorafenib in patients with advanced hepatocellular carcinoma who progressed or were resistant to the treatment.
2. Cabozantinib
Cabozantinib is a new multi-targeted antitumor drug initially used for the treatment of advanced medullary thyroid cancer and kidney cancer. The CELESTIAL clinical study in advanced hepatocellular carcinoma showed a median overall survival of 10.2 months in the cabozantinib-treated group and 8.0 months in the placebo group (HR=0.76, p=0.005); disease control rates were 64% and 33% in the two groups, respectively. In January 2019, the U.S. FDA officially approved cabozantinib for the second-line treatment of patients with advanced hepatocellular carcinoma. At present, because cabozantinib has not yet been formally approved by the CFDA, cabozantinib cannot be prescribed as second-line targeted therapy for hepatocellular carcinoma in China.
3.Remolimumab
Patients with advanced hepatocellular carcinoma with elevated AFP have a very poor prognosis. After the failure of sorafenib treatment, about half of the patients have AFP ≥ 400ng/ml, and effective therapeutic drugs are needed for such patients. Remolimumab is a human IgG1 monoclonal antibody that inhibits the activation of VEGFR2 ligands. In the previous randomized, controlled phase III REACH clinical study, ramolutumab failed to significantly improve patient overall survival as second-line treatment for patients with sorafenib-progressive advanced hepatocellular carcinoma, but prolonged overall survival was achieved in a subgroup with baseline AFP ≥ 400 ng/ml. Based on the results of the REACH study subgroup analysis, the REACH-2 clinical study further evaluated the efficacy and safety of ramolutumab in patients with advanced hepatocellular carcinoma with AFP ≥ 400 ng/ml. The results of the study showed that the median survival of patients in the ramolutumab-treated group was longer than that in the placebo group (8.5 months vs. 7.3 months, HR=0.710, P=0.0199). The progression-free survival outcome suggested that the ramolutumab-treated group also outperformed the placebo group (2.8 months vs. 1.6 months; HR=0.452, P<0.001). The REACH-2 clinical study is the first phase III clinical study to obtain positive results in a population of patients with hepatocellular carcinoma based on tumor marker screening, bringing new options for second-line treatment of patients with elevated baseline AFP.
How to choose the appropriate molecular targeted drugs for patients with advanced liver cancer?
The selection of targeted drugs for hepatocellular carcinoma requires a comprehensive judgment based on the patient’s tumor condition, liver function, physical status, risk of side effects occurrence and economic factors. Sorafenib, as the first molecular targeted drug for hepatocellular carcinoma to enter medical insurance, has experienced more than ten years of clinical practice to confirm its efficacy and safety, and has become the most commonly used first-line targeted drug for advanced hepatocellular carcinoma patients in China. Lenvatinib is a newly approved molecular targeted drug in 2018, whose therapeutic efficacy is not inferior to sorafenib and is more effective in hepatocellular carcinoma patients with hepatitis B infection background, but it has not yet entered into medical insurance and is a self-financed targeted drug. Regifenib is the preferred second-line targeted therapy after failure of sorafenib treatment. Regifenib has a broader therapeutic target than sorafenib, and its side effects such as hand-foot syndrome, diarrhea, and hypertension are more pronounced than sorafenib. Therefore, for patients with hepatocellular carcinoma who cannot tolerate the side effects of sorafenib, treatment with regifenib is also not recommended. For this group of patients, if the methemoglobin is >400ng/mL, treatment with ramolutumab can be considered. For patients with negative methemoglobin, cabozantinib is currently the second-line targeted therapy of choice. However, these two targeted drugs are currently only approved in the US and EU, and domestic patients need to wait for CFDA approval before they can purchase the drugs through regular prescriptions.
If both first-line and second-line targeted therapies have failed, how can follow-up treatment be carried out?
Currently, there is no standard third-line targeted therapy for advanced liver cancer, so treatment for patients who have failed second-line targeted therapy has become a challenge for advanced liver cancer treatment. At present, the solutions are mainly divided into two aspects, one is to participate in clinical studies of new drugs, such as clinical studies of immunotherapy combined with molecular targeted therapy, clinical studies of immunotherapy combined with chemotherapy, clinical studies of combination therapy between immune checkpoint inhibitors; the second is to adopt the combination mode between targeted therapy and local therapy. In the process of targeted therapy, corresponding local treatment is given according to the tumor progression, such as targeted therapy combined with interventional or hepatic artery infusion chemotherapy, bronchial artery infusion chemotherapy, immunotherapy combined with radiofrequency, local radiotherapy and other treatment strategies. The treatment mode of advanced hepatocellular carcinoma is different from that of other tumor types. Patients with hepatocellular carcinoma that has developed distant metastasis can be treated for their local liver lesions on the basis of systemic treatment; if there is no progression of extrahepatic lesions but only intrahepatic lesions, intrahepatic local treatment can be administered first; when extensive intrahepatic progression cannot implement local treatment, systemic treatment measures can be adjusted.
Conclusion
With the emergence of targeted therapy and emerging immunotherapy for liver cancer, the treatment of mid- to late-stage liver cancer has entered the era of diversification and multi-modality, and the emergence of many new molecular targeted drugs has greatly prolonged the survival of patients with advanced liver cancer. In the future, the treatment mode of advanced liver cancer will change to chronic disease management mode. The Department of Hepatology and Oncology of Zhongshan Hospital of Fudan University features comprehensive treatment of middle and late stage liver cancer, adheres to the concept of whole process management of liver cancer treatment, combines local and systemic treatment of liver cancer, fully evaluates the general condition of patients, underlying liver disease and biological characteristics of tumor, based on which a reasonable and complete planning plan is formulated, and dynamically observes the treatment response of patients, revises and constantly improves the treatment plan in a timely manner In addition, we carry out individualized treatment with multidisciplinary combination to bring better survival benefits to the majority of liver cancer patients.