Recently, his neighbor, Uncle He, had a poor appetite and vague discomfort in his liver area. His sons and daughters all exploded and rushed to the Internet to find out how to cure him. The eldest son said that surgery is the most reliable way to remove liver cancer; the second son said that the latest minimally invasive ablation and interventional therapy can cure liver cancer without surgery; the youngest daughter said that her father is too old to toss and turn, and that liver cancer can be cured by taking targeted drugs and immunization, so she should consult internal medicine. We discussed and discussed, but we lost the direction.
There are so many options for liver cancer treatment, so how can liver cancer patients choose the best treatment plan?
Surgical treatment of liver cancer actually includes 2 aspects, that is, surgical resection of tumor or liver transplantation. Whether it is surgical resection or liver transplantation, there is a prerequisite that the tumor found is in early stage and has no metastasis, so that the surgical result is better for such patients. So what kind of liver cancer is early stage liver cancer?
According to the 2019 edition of the “Diagnostic and Treatment Standards for Primary Liver Cancer”, a single tumor or multiple tumors within 3 tumors without blood vessels, lymph nodes or distant metastases with good liver function is considered early stage liver cancer and suitable for surgical resection. A comprehensive evaluation of the patient’s general condition and liver reserve function should be conducted before surgery. Good liver function and sufficient volume of the remaining liver after resection are necessary conditions for surgical resection.
For patients with early stage liver cancer who have poor liver function and cannot tolerate surgical resection, liver transplantation is the best choice. With regard to the indications for liver transplantation for liver cancer, the Milan criteria and the University of California, San Francisco (UCSF) criteria are mainly used internationally. In China, there are Hangzhou criteria, Shanghai Fudan criteria, Huaxi criteria and Sanya consensus, etc. These criteria are consistent for the absence of large vessel invasion, lymph node metastasis and extrahepatic metastasis, but the requirements for the size and number of tumors are not the same. At this stage, the UCSF criteria are recommended by China’s Health Care Commission norms, namely, single tumor diameter ≤ 6.5 cm; tumors ≤ 3, of which the largest tumor diameter ≤ 4.5 cm and the total tumor diameter ≤ 8 cm; and no large vessel invasion. Patients with liver cancer who meet the criteria for transplantation can achieve a five-year survival rate of 70% after transplantation.
After talking about surgical treatment of liver cancer, what about tumor ablation?
Liver transplantation can achieve radical cure for early stage liver cancer patients who have poor liver function and cannot tolerate surgical resection. However, liver transplantation is complicated, technically demanding, and liver sources are scarce, transplantation is expensive, and long-term immunosuppressive drugs are required after surgery, which is a great challenge to patients and families. For patients with early stage liver cancer who are not eligible for liver transplantation, or are of advanced age and have combined heart and lung chronic diseases, percutaneous minimally invasive ablation therapy is the best choice.
Percutaneous tumor ablation is to induce necrosis of tumor cells and local inactivation of tumor tissues by applying chemical ablation, thermal ablation or cryoablation techniques to tumor tissues through percutaneous puncture under the guidance of medical imaging equipment such as ultrasound or CT or MRI. The inactivated tumor tissue does not need to be removed, but will gradually shrink and become a scar, and the efficacy is equivalent to surgical resection. The most commonly applied clinical ablation treatment for liver cancer is mainly thermal ablation, including radiofrequency ablation, microwave ablation, laser ablation, high-energy focused ultrasound and irreversible electroporation (nano-knife). During the treatment process, medical imaging equipment “navigates” the surgery, precisely locates the tumor, and eliminates the tumor with maximum protection of organ and tissue functions, so it has the characteristics of less trauma, better efficacy, shorter recovery period and less complications.
Compared with surgical resection, what are the advantages of percutaneous ablation for small liver cancer?
1. For liver cancer with tumor diameter less than 3 cm, ablation has exact efficacy and is less invasive, without opening the abdomen, avoiding the trauma of major surgery.
2. Fast recovery after surgery, which can be discharged from hospital in 1-2 days after surgery and has little impact on life quality.
3, high safety, the incidence of postoperative complications is lower than that of open surgery.
4. wider indications than surgical resection, not only suitable for primary liver cancer, but also for multiple metastatic liver cancers that cannot be removed by surgery.
5. ablation therapy can be repeated, especially suitable for multiple recurrent tumor lesions.
6. it requires less liver function and cardiopulmonary function, and is suitable for patients with poor liver function or other organ insufficiency that cannot be surgically resected.
What is interventional treatment for liver cancer about again?
Interventional treatment for liver cancer, also called hepatic artery chemoembolization (TACE), is a minimally invasive treatment method of injecting chemotherapeutic drugs and vascular embolic agents into the tumor vessels by making a 3-5 mm incision on the skin and inserting a tube to the hepatic artery through the femoral artery of the thigh or the radial artery at the wrist without making an incision.
As China is a large country with hepatitis B, most of the liver cancer patients are infected with hepatitis B and start the disease. Since liver cancer starts insidiously and there are usually no symptoms in early stage, most patients are diagnosed with middle to late stage liver cancer, with large tumor diameter, or with intrahepatic vascular invasion or distant metastasis, and have no chance of surgical resection or ablation treatment. This group of patients is the main group of patients who receive interventional treatment.
The advantages of interventional treatment for hepatocellular carcinoma are.
1. selective infusion of chemotherapeutic drugs through hepatic artery, the concentration of chemotherapeutic drugs is tens of times higher than that of intravenous chemotherapy, but the toxicity is less than that of systemic chemotherapy. Patients with good efficacy after interventional surgery have rapid decrease of methemoglobin, shrinkage of masses and pain relief.
2. Interventional surgery is minimally invasive treatment, local anesthesia is sufficient, and the surgical incision is only a few millimeters, which can be performed even for elderly and frail patients.
3, most patients recover faster after intervention, treatment is better tolerated, and treatment can be repeated in about 4-6 weeks.
4. the cost of interventional treatment is low, and some large hepatocellular carcinomas that cannot be surgically removed can be surgically removed after tumor shrinkage by interventional treatment.
The most common adverse effect of TACE treatment is post-embolization syndrome, which mainly manifests as fever, pain, nausea and vomiting. In addition, there are also adverse reactions such as bleeding at the puncture site, white blood cell drop, transient liver function abnormalities, and renal function impairment. Adverse reactions after interventional therapy last 5-7 d. Most patients can fully recover after symptomatic treatment.
Finally, let’s talk about targeted therapy for hepatocellular carcinoma.
As a systemic disease, hepatocellular carcinoma can be treated by various local treatments in early or middle stage, including surgical resection, liver transplantation, radiofrequency ablation and interventional methods. For patients with advanced hepatocellular carcinoma who have developed vascular, lymph node or distant metastasis, targeted therapy is the standard treatment strategy.
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.
What are the current molecular targeted therapeutic drugs for liver cancer?
First-line molecular targeted drugs.
1.Sorafenib
Sorafenib is the first first-line targeted therapy drug approved by the US FDA for advanced hepatocellular carcinoma. The SHARP clinical study conducted in Europe and the United States and the ORIENTAL international multicenter clinical study conducted in the Asia-Pacific region have confirmed the efficacy and safety of sorafenib in advanced hepatocellular carcinoma. As an oral tyrosine kinase inhibitor, sorafenib works mainly by inhibiting tumor proliferation and tumor angiogenesis, which can effectively prolong the survival time of patients with advanced hepatocellular carcinoma.
2.Lenvatinib
After sorafenib was approved as the first-line drug for advanced hepatocellular carcinoma in 2007, a number of anti-vascular molecular target drugs have been launched in international large phase III clinical trials, such as brinib (Brivanib), sunitinib (Sunitinib), linifanib (Linifanib), etc. However, 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 been approved by the FDA in Japan, Europe and the United States, and China, and has been included in the 2019 edition of the Health Care Commission’s Primary Liver Cancer Treatment Guidelines and the CSCO Primary Liver Cancer Treatment Guidelines as a first-line recommended target drug together with sorafenib.
Second-line molecular targeted drugs.
Many patients with hepatocellular carcinoma are initially effective with sorafenib and later develop drug resistance, and then need to be treated with second-line targeted drugs. Regorafenib is a fluorogenic drug of sorafenib, and its molecular structure is similar to sorafenib, which can inhibit multiple kinases in the tumor microenvironment and has 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.
For the second-line treatment of other advanced hepatocellular carcinoma, the US FDA approved nabolutumab (Nivolumab) and pembrolizumab (Pembrolizumab) for patients with hepatocellular carcinoma that progressed after previous sorafenib treatment or were unable to tolerate sorafenib. Currently, immune checkpoint inhibitors developed independently by Chinese companies, such as carrilizumab, tremelimumab and sindilizumab, are under clinical investigation. Combination regimens of immunotherapy with targeted drugs, chemotherapeutic agents, and local therapies are also being explored. The clinical study of the domestic small molecule anti-angiogenic targeted drug Apatinib for second-line treatment of liver cancer patients has also been successful recently, and is expected to be approved for second-line targeted treatment indications for liver cancer by the end of the year.
In addition, the FDA approved cabozantinib for patients with hepatocellular carcinoma progressing on first-line targeted therapy and approved ramolutumab for second-line treatment of patients with hepatocellular carcinoma with serum AFP levels ≥400ng/mL. However, neither of these drugs is available in China.
There are numerous treatment options for hepatocellular carcinoma. After reading this article, we hope to clarify the concept – the patient’s liver function basis, age, physical condition, tumor size and number, presence of metastasis and other chronic underlying diseases determine the treatment strategy for hepatocellular carcinoma. Prior to tumor treatment, a comprehensive and individualized evaluation at an experienced center is recommended to select the most appropriate treatment strategy for the patient in order to achieve the best survival benefit.